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All life forms typically possess homochirality, with rare exceptions. In the case of peptides and proteins, only L-amino acids are known to be encoded by genes. Nevertheless, D-amino acids have been identified in a variety of peptides, synthesized by animal cells. They include neuroexcitatory and neuroprotective peptides, cardioexcitatory peptides, hyperglycemic hormones, opioid peptides, antimicrobial peptides, natriuretic and defensin-like peptides, and fibrinopeptides. This article is a review of their occurrence, structure and bioactivity. It further explores the pharmacology and potential medical applications of some of the peptides., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chronological age is considered one of the major risk factors for cardiovascular disease and mortality. The study aimed to evaluate the transcriptional levels of the natriuretic peptides (NP), endothelin (ET)-1, adrenomedullin (ADM), their receptors and long non-coding (Lnc) RNA MIAT, MALAT-1, CARMEN and XIST in rat cardiac tissue as cardiovascular biomarkers of aging. Three groups of male Wistar rats were studied: A (n = 6; young), B (n = 13; adult), C (n = 10; old). Total RNA was extracted from left ventricle and analyzed by Real-Time PCR. Echocardiographic and histological analyses were performed. A significant increase of Atrial NP (ANP) and Brain NP (BNP) mRNA was observed in C while C-type NP (CNP) remained in a steady-state in B and C; ET-1 mRNA increased significantly as a function of age. Any difference was observed for NP receptors. ETA expression was statistically lower in B than A while ETB were similar in all the three groups. The ADM showed an opposite trend to that of the other peptides decreasing significantly as a function of age and presenting a counter-regulation of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein (RAMP)-2. LncRNA transcripts decreased significantly as a function of age except for XIST. ADM and LncRNA trend suggest that the animals are subjected to "successful aging" as also confirmed by histological analysis. Applying a multivariate logistic regression analysis, only LnANP (p = 0.003) and LnADM (p = 0.023) resulted significantly associated with aging identifying them, for the first time, as independent markers of aging. The study underlining the importance of a multi-label biomolecular approach in the evaluation of aging., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The left atrial appendage (LAAp) resection is an effective treatment approach to reduce the risk of thromboembolism in patients with atrial fibrillation., Objective: To study was to study the impact of removing atrial appendages in the production of natriuretic peptides (NPs) in conditions of volume overload and to develop an experimental model of LAAp resection., Materials and Methods: In a swine model of ischemic heart failure (HF), serum NP levels were measured before (Basal-1A) and after (Basal-1B) a fluid overload. Animals were grouped as follows: (0) preserved appendages, (1) resected LAAp, and (2) both atrial appendages resected. Levels of NP were measured before (2A) and after a fluid overload (2B)., Results: Furin levels were higher in Group 0-2A than in Group 2-2A, and a significant increase was found in Group 0-2B compared to Groups 1-2B and 2-2B. Corin levels increased in Basal-1B versus Basal-1A. Atrial NP (ANP) decreased in Basal-1B compared to Basal-1A. After HF induction, ANP increased in Groups 2-2A and 2-2B., Conclusions: Resection of atrial appendages drastically modifies the natriuretic mechanisms of cardiac homeostasis, especially after a fluid overload challenge. Herein, we describe the face and predictive validation of an animal model of atrial appendage resection useful to investigations in translational medicine., (Copyright: © 2020 Permanyer.)

Anatolian ground squirrel (Spermophilus xanthoprymnus) is a true hibernator. This animal transiently reduces pulmonary function during hibernation. Continuance of pulmonary function is very important to survive ground squirrels during the hibernation. Natriuretic peptides may be key players in the modulation of pulmonary hemostasis. However, NPs' role in pulmonary function during hibernation remains unclear. We aimed to investigate the localization and distribution of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) in squirrel lungs during pre-hibernation and hibernation periods using immunohistochemistry. Our immunohistochemical data indicate that ANP, BNP, and CNP were produced by the mucosal epithelium of terminal and respiratory bronchioles, smooth muscle cells in the lamina propria of terminal bronchioles and vascular smooth muscle cells, alveolar type II cells, and macrophages. ANP immunoreactivity was weaker than BNP and CNP immunoreactivities in these cells. The results also demonstrate that the number of ANP, BNP and CNP positive alveolar type II cells tended to increase, although statistically non-significant, during the hibernation period, but the expression of NPs in other pulmonary cells is unaffected by hibernation. This study firstly investigates ANP, BNP and CNP distribution in the Anatolian ground squirrel lung. However, further studies are required to dissect their functional roles during the hibernation., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Aim: To determine whether intestinal expression of guanylate cyclase activator 2A (GUCA2A) and guanylate cyclase activator 2B (GUCA2B) genes is regulated in obese humans following Roux-en-Y gastric bypass (RYGB), and to evaluate the corresponding guanylin (GN) and uroguanylin (UGN) peptides for potentially contributing to the beneficial metabolic effects of RYGB., Methods: Enteroendocrine cells were harvested peri- and post-RYGB, and GUCA2A/GUCA2B mRNA expression was compared. GN, UGN and their prohormones (proGN, proUGN) were administered subcutaneously in normal-weight mice to evaluate effects on food intake and glucose regulation. The effect of pro-UGN or UGN overexpression, using adeno-associated virus (AAV) vectors, was assessed in diet-induced obese (DIO) mice. Intracerebroventricular administration of GN and UGN was performed in rats for assessment of putative centrally mediated effects on food intake. GN and UGN, as well as their prohormones, were evaluated for effects on glucose-stimulated insulin secretion (GSIS) in rat pancreatic islets and perfused rat pancreas., Results: GUCA2A and GUCA2B mRNA expression was significantly upregulated in enteroendocrine cells after RYGB. Peripheral administration of guanylins or prohormones did not influence food intake, oral glucose tolerance, and GSIS. Central administration of GN and UGN did not affect food intake in rats. Chronic AVV-mediated overexpression of UGN and proUGN had no effect on body weight or glucose homeostasis in DIO mice., Conclusion: GN and UGN, as well as their prohormones, do not seem to play a significant role in body weight regulation and glycemic control, suggesting that guanylin-family peptides do not show promise as targets for the treatment of obesity or diabetes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Uroguanylin (UGN) is a potential target in the fight against obesity. The mature protein is released after enzymatic cleavage from its natural precursor, proUGN. UGN is mostly produced in the gut, and its production is regulated by nutritional status. However, UGN is also produced in other tissues such as the kidneys. In the past, UGN has been widely studied as a natriuretic peptide owing to its involvement in several different pathologies such as heart failure, cancer and gastrointestinal diseases. However, recent studies have suggested that UGN also acts as a regulator of body weight homeostasis because it modulates both food intake and energy expenditure. This ultimately results in a decrease in body weight. This action is mediated by the sympathetic nervous system. Future studies should be directed at the potential effects of UGN agonists in regulating body weight in human obesity., (© 2018 Society for Endocrinology.)

Recently we found that guanylin (Gn) and its receptor, guanylyl cyclase C (GC-C), are uniquely expressed in the mesenteric macrophages of some diet-resistant rats and that double-transgenic (dTg) rats overexpressing Gn and GC-C in macrophages demonstrate reduced fatty acid synthase and fat accumulation in fat tissue even when fed a high-fat diet (HFD). Lipid accumulation and fatty acid synthase mRNA levels in cocultured dTg rat adipocytes and macrophages were reduced compared with those in adipocytes cultured with WT rat macrophages. Here, we investigated whether Interleukin-15 (IL-15) derived from Gn-GC-C-expressing macrophages regulates lipid accumulation in adipocytes. IL-15 inhibited fatty acid synthase and lipid accumulation via STAT5 in cultured adipocytes. IL-15 mRNA and protein levels in the mesenteric fat of HFD-fed dTg rats were significantly higher than those of HFD-fed WT rats. Phosphorylated STAT5 levels in the mesenteric fat of HFD-fed dTg rats were increased compared with those of HFD-fed WT rats. In addition, the mRNA level of fatty acid synthase in the mesenteric fat was lower in HFD-fed dTg rats than in HFD-fed WT rats. These results support the hypothesis that IL-15 secreted from Gn-GC-C-expressing macrophages contributes to the inhibition of fatty acid synthase and lipid accumulation in adipocytes, leading to obesity resistance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Guanylin (GN) and uroguanylin (UGN), through activation of guanylyl cyclase C (GCC), serve to control intestinal fluid homeostasis. Both peptides are produced in the intestinal epithelium, but their cellular origin has not been fully charted. Using quantitative PCR and an improved in situ hybridization technique (RNAscope), we have assessed the expression of GN (Guca2a), UGN (Guca2b), and GCC (Gucy2c) in mouse intestine. In the crypts of Lieberkühn, expression of Guca2a and Guca2b was restricted to cells of secretory lineage, at the crypt's base, and to a region above, previously identified as a common origin of cellular differentiation. In this compartment, comparatively uniform levels of Guca2a and Guca2b expression were observed throughout the length of the gut. In contrast, Guca2a and Guca2b expression in the villus-surface region was more variable, and reflected the distinct, but overlapping expression pattern observed previously. Accordingly, in jejunum and ileum, Guca2a and Guca2b were abundantly expressed by enterocytes, whereas in colon only Guca2a transcript was found in the surface region. In duodenum, only low levels of Guca2b transcript were observed in columnar cells, and Guca2a expression was restricted entirely to cells of the secretory lineage. Gucy2c was shown to be expressed relatively uniformly along the rostrocaudal and crypt-villus axes and was also found in the duodenal glands. Our study reveals novel aspects of the cellular localization of the GCC signaling axis that, apart from its role in the regulation of fluid balance, link it to pH regulation, cell cycle control, and host defense., Competing Interests: The authors declare that they have no conflict of interest.

The peptide uroguanylin (Ugn) is expressed at significant levels only in intestine and kidney, and is stored in both tissues primarily (perhaps exclusively) as intact prouroguanylin (proUgn). Intravascular infusion of either Ugn or proUgn evokes well-characterized natriuretic responses in rodents. Furthermore, Ugn knockout mice display hypertension and salt handling deficits, indicating that the Na(+) excretory mechanisms triggered when the peptides are infused into anesthetized animals are likely to operate under normal physiological conditions, and contribute to electrolyte homeostasis in conscious animals. Here, we provide strong corroborative evidence for this hypothesis, by demonstrating that UU gnV (the rate of urinary Ugn excretion) approximately doubled in conscious, unrestrained rats consuming a high-salt diet, and decreased by ~15% after salt restriction. These changes in UU gnV were not associated with altered plasma proUgn levels (shown here to be an accurate index of intestinal proUgn secretion). Furthermore, enteric Ugn mRNA levels were unaffected by salt intake, whereas renal Ugn mRNA levels increased sharply during periods of increased dietary salt consumption. Together, these data suggest that diet-evoked Ugn signals originate within the kidney, rather than the intestine, thus strengthening a growing body of evidence against a widely cited hypothesis that Ugn serves as the mediator of an entero-renal natriuretic signaling axis, while underscoring a likely intrarenal natriuretic role for the peptide. The data further suggest that intrarenal Ugn signaling is preferentially engaged when salt intake is elevated, and plays only a minor role when salt intake is restricted., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Background: The cardiac natriuretic peptides (NPs), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), have central roles in sodium and blood pressure regulation. Extracardiac factors (e.g., obesity and diabetes) influence NP production, potentially altering cardiovascular responses to volume and pressure stress., Objectives: This study examined the effects of acute carbohydrate intake on the NP system in humans, and investigated underlying mechanisms., Methods: Normotensive subjects (N = 33) were given a high-carbohydrate shake. Venous blood was sampled to measure N-terminal (NT)-proANP and NT-proBNP levels. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and HepG2 cells were treated with glucose, and expression levels of NPs and micro ribonucleic acid 425 (miR-425), a negative regulator of ANP, were examined. The role of nuclear factor kappa B (NF-κB) in the glucose-mediated effects was investigated using a NF-κB inhibitor and expression plasmids encoding NF-κB subunits., Results: We observed a 27% reduction in the levels of circulating NT-proANP (p < 0.001, maximal at 6 h) after carbohydrate challenge, with no effect on NT-proBNP levels in our human subjects. Glucose treatment of hESC-CMs for 6 h and 24 h increased levels of the primary transcript of miR-425 (pri-miR-425) and mature miR-425. A corresponding decrease in NPPA messenger RNA levels was also observed at both time points. Overexpression of NF-κB subunits in H9c2 cardiomyocytes increased miR-425 levels, whereas inhibition of NF-κB abrogated the glucose-mediated increase in pri-miR-425 levels in HepG2 cells., Conclusions: Acute carbohydrate challenge is associated with a reduction in ANP production. The mechanism appears to involve a glucose-induced increase in the expression of miR-425, mediated by NF-κB signaling., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The molecular mechanisms leading to gastric carcinogenesis still remain unclear. Recently, several studies demonstrated that over-expression of guanylyl cyclase C (GCC) has been detected in intestinal-type gastric cancer (GC) and precursor lesions. Our objective was to explore the expression levels of GCC and endogenous ligands guanylin (GN) and uroguanylin (UGN) and the correlation between Helicobacter pylori (H. pylori) and GCC, GN, and UGN expressions in patients at different stages from normal mucosa to superficial gastritis, atrophic gastritis, intestinal metaplasia (IM), dysplasia, and finally adenocarcinoma. The expression of GCC and GN was absent in the distal normal gastric tissues and superficial gastritis in all cases, whereas they were measured in IM, dysplasia, and GC. The expression of GCC and GN was closely related to intestinal-type GC. From superficial gastritis to gastric carcinomas, the H. pylori positive rate was 19.7, 33.3, 69.6, 80.0, and 82.1%, respectively. The positive correlation was found between GCC and GN in IM, dysplasia, and GC. Also, the positive correlation was found between GCC, GN, and H. pylori infection in them. These results demonstrate that the detection of GCC and GN will be beneficial to diagnosis human gastric carcinoma and precancerous lesions. Ectopic expression of GCC and GN in human gastric mucosa and H. pylori infection may play an important role in the carcinogenesis of the intestinal-type GC.

Natriuretic peptides elicit vasodilation, increased sodium excretion and concomitant diuresis, and counteract the RAAS. In the heart itself, natriuretic peptides may also act anti-inflammatory and antifibrotic. This has led to the pursuit of natriuretic peptides and chemically modified peptides as adjunctive therapy in myocardial ischaemia. However, natriuretic peptide infusion may also influence the endogenous natriuretic peptide response and lipid accumulation. We hypothesised that a) natriuretic peptide infusion (BNP and CD-NP) is cardiomyocyte protective, b) affects the endogenous response, and c) facilitate cardiac lipid accumulation. We examined these effects in a minimally invasive porcine model of regional cardiac ischaemia and reperfusion. The studies were supplemented by a 48-hour porcine model of ischemia and reperfusion as well as an in vitro study of BNP administered in a HL-1 cell model of "ischaemia/reperfusion". Infarct size was determined by TTC staining, plasma troponin T release, and total RNA integrity in cardiac tissue samples. The endogenous response was assessed by a processing-independent proANP immunoassay and mRNA quantitation. Lipids in plasma and myocardial tissue were determined by TLC. The studies show that natriuretic peptides decrease cardiomyocyte damage, possibly partly through indirect mechanisms. Furthermore, BNP infusion completely inverts the endogenous response, whereas CD-NP infusion does not. Finally, both natriuretic peptides increase plasma free fatty acids, which is associated with an increased cardiac lipid accumulation in non-ischaemic myocardium. In conclusion, the studies suggest that natriuretic peptides are beneficial in terms of reduced cardiac injury. In addition, the endogenous natriuretic peptide response is inverted. The results advocate for pursuing natriuretic peptide treatment in ischaemia/reperfusion damage. However, the metabolic consequences in a cardiac tissue challenged by ischaemia should be pursued before testing the peptides in patients.

Guanylin, a bioactive intestinal peptide, is involved in the cystic fibrosis transmembrane conductance (CFTR)-regulated electrolyte/water secretion in various epithelia. In the present work we report on the expression and cellular localization of guanylin and its affiliated signaling and effector proteins, including guanylate cyclase C (Gucy2c), Proteinkinase GII (Pkrg2), CFTR and the solute carrier family 4, anion exchanger, member 2 (Slc4a2) in the hepatobiliary system of rat and guinea pig. Localization studies in the liver and the gallbladder revealed that guanylin is located in the secretory epithelial cells of bile ducts of the liver and of the gallbladder, while Gucy2c, Pkrg2, CFTR, and Slc4a2 are confined exclusively to the apical membrane of the same epithelial cells. Based on these findings, we assume that guanylin is synthesized as an intrinsic peptide in epithelial cells of the hepatobiliary system and released luminally into the hepatic and cystic bile to regulate electrolyte secretion by a paracrine/luminocrine signaling pathway.

Plant natriuretic peptides (PNPs) are signalling molecules that are secreted into the apoplast particularly under conditions of biotic and abiotic stress.  At the local level, PNPs modulate their own expression via feed forward and feedback loops to enable tuning of the response at the transcript and protein level and to prevent over-expression.  PNPs also employ a systemic signal, possibly electrical, to rapidly alter photosynthesis and respiration not only in treated leaves but also in upper and lower leaves thereby modulating and integrating physiological responses at the level of the whole plant.

Classic and modern data on natriuretic peptide hormones that are synthesized in cardiac atria and participate in hemodynamic and water-salt balance regulation are summarized in this paper. Cumulated data on polypeptide variety, their structure, intracellular syntheses, physiological effects and concentration alterations during model experiments and cardiovascular pathology are presented. Unsolved problems including methods of plasma peptides concentration measurements, their role in heart failure development, and their clinical significance are discussed.

Nitric oxide relaxes myometrium in a cGMP-independent manner. Although cGMP activates its cognate kinase, this is not required for the inhibitory effect of nitric oxide. Thus, nitric oxide-mediated cGMP elevation does not enjoy the same set of substrates as it does in other smooth muscles. To further understand the regulation of relaxation of uterine muscle by cGMP, we have studied the actions of peptide-mediated cGMP action in guinea pig myometrium. We used both functional and biochemical studies of the action of the particulate guanylyl cyclase activator uroguanylin and its receptor, particulate guanylyl cyclase type C, to address the relationship between cGMP elevation acting in the membrane signaling domain to that of the nonmembrane region of the cell. Uroguanylin relaxed oxytocin-induced contractions in a dose-dependent fashion only in pregnant myometrium. Both relaxation and cGMP accumulation after uroguanylin stimulation were blocked by the putative particulate guanylyl cyclase type C inhibitors 2-chloro-ATP and isatin (1H-indole-2,3-dione), but not by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-A]quinoxalin-1-one (ODQ). Uroguanylin stimulated cGMP accumulation only in the pregnant myometrium. Caveolin-1 expression increased in pregnancy toward term. In the caveolin-1-containing membrane domain, uroguanylin, but not the nitric-oxide donor, led to the elevation of cGMP that was insensitive to ODQ. Particulate guanylyl cyclase C was expressed and prouroguanylin was detected in pregnant myometrium. We conclude that a uroguanylin-particulate cyclase-cGMP relaxation pathway is present and cGMP is compartmented in myometrium. The agonist-mediated selectivity of relaxation to cGMP is of fundamental pharmacological interest in understanding signal transduction in smooth muscle.

Cardiac-derived peptide hormones were identified more than 25 years ago. An astonishing amount of clinical studies have established cardiac natriuretic peptides and their molecular precursors as useful markers of heart disease. In contrast to the clinical applications, the biogenesis of cardiac peptides has only been elucidated during the last decade. The cellular synthesis including amino acid modifications and proteolytic cleavages has proven considerably more complex than initially perceived. Consequently, the elimination phase of the peptide products in circulation is not yet well characterized. An ongoing characterization of the molecular heterogeneity will help appreciate the biosynthetic capacity of the endocrine heart and could introduce new diagnostic possibilities. Notably, different biosynthetic products may not be equal markers of the same pathophysiological processes. An inefficient post-translational prohormone maturation will also affect the biology of the cardiac natriuretic peptide system. This review aims at summarizing the myocardial synthesis of natriuretic peptides focusing on B-type natriuretic peptide, where new data has disclosed cardiac myocytes as highly competent endocrine cells. The structurally related atrial natriuretic peptide will be mentioned where appropriate, whereas C-type natriuretic peptide will not be considered as a cardiac peptide of relevance in mammalian physiology.

Although deoxycorticosterone acetate (DOCA)-salt hypertension is a volume dependent model of hypertension, it shows polyuria and natriuresis. It is expected that dysregulation of aquaporin water channels (AQPs) and sodium transporters associated with natriuretic peptide (NP) system may play an escape role in sodium retaining state. One week after left unilateral nephrectomy, rats were subcutaneously implanted with silastic DOCA (200 mg/kg) strips. Physiologic saline was supplied as a drinking water to all animals. 4 weeks after operation, the protein expression of AQPs, sodium transporters, and endopeptidase (NEP) was determined in the kidneys by semiquantitative immunoblotting and immunohistochemistry. The mRNA expression of NP system was determined by real-time polymerase chain reaction. The amount of urinary ANP excretion was measured by radioimmunoassay. In DOCA-salt rats, urine osmolality was decreased while urinary excretion of sodium was increased. The expression of AQP1-3 as well as that of alpha-1 subunit of Na,K-ATPase, NHE3, NKCC2 and NCC was decreased in the kidney. The mRNA expression of ANP, brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) was increased in the kidney. The expression of NEP was decreased, and urinary ANP excretion was increased. Downregulation of AQPs and sodium transporters may contribute to mineralocorticoid escape in DOCA-salt hypertension. Increased expression of natriuretic peptides associated with downregulation of NEP may play a role in natriuresis.

Natriuretic peptides (NPs) and their receptors (NPRs) comprise an evolutionarily conserved signaling system with profound physiological effects on vertebrate renal and cardiovascular systems. Some NPs (ANP, BNP and VNP) are primarily of cardiac origin whereas CNP is common in the brain. In mammals, non-traditional sites of NPs synthesis, BNP in brain and CNP in atrium, appear to have complementary actions. In the present study, trout were chronically adapted to freshwater (FW) (a volume-loading, salt-depleting environment), saltwater (SW) (a volume-depleting, salt-loading environment), FW and fed a high-salt diet (FW-HSD) (a volume- and salt-loading regime) or acutely volume depleted or expanded by hemorrhage or infusion with dialyzed plasma to perturb volume homeostasis. The responses of brain and atrial BNP and CNP mRNA, pro-peptide, NPR-A and NPR-B were evaluated using quantitative PCR and western analysis. Brain pro-BNP and NPR-A was increased in FW-HSD trout and decreased in SW trout. Brain pro-CNP was largely unaffected whereas NPR-B mRNA was increased in FW-HSD trout. Atrial CNP, although produced at lower levels than other cardiac NPs, was markedly elevated in chronically (FW-HSD) and acutely volume expanded trout (dialyzed-plasma infusion) whereas decreased in hemorrhaged trout. These findings indicate that non-traditional NP synthesis sites in the trout probably complement the broad hypovolemic and hypotensive actions of traditional (cardiac) NP synthesis sites in response to volume expansion but not to plasma osmolarity. This supports the hypothesis that the piscine and mammalian NP systems are fundamentally similar and appear to protect the heart from volume overload.

Background: Some studies have shown that metformin activates AMP-activated protein kinase (AMPK) and has a potent cardioprotective effect against ischemia/reperfusion injury. Because AMPK also is activated in animal models of heart failure, we investigated whether metformin decreases cardiomyocyte apoptosis and attenuates the progression of heart failure in dogs., Methods and Results: Treatment with metformin (10 micromol/L) protected cultured cardiomyocytes from cell death during exposure to H2O2 (50 micromol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and flow cytometry. Continuous rapid ventricular pacing (230 bpm for 4 weeks) caused typical heart failure in dogs. Both left ventricular fractional shortening and left ventricular end-diastolic pressure were significantly improved in dogs treated with oral metformin at 100 mg x kg(-1) x d(-1) (n=8) (18.6+/-1.8% and 11.8+/-1.1 mm Hg, respectively) compared with dogs receiving vehicle (n=8) (9.6+/-0.7% and 22+/-0.9 mm Hg, respectively). Metformin also promoted phosphorylation of both AMPK and endothelial nitric oxide synthase, increased plasma nitric oxide levels, and improved insulin resistance. As a result of these effects, metformin decreased apoptosis and improved cardiac function in failing canine hearts. Interestingly, another AMPK activator (AICAR) had effects equivalent to those of metformin, suggesting the primary role of AMPK activation in reducing apoptosis and preventing heart failure., Conclusions: Metformin attenuated oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK. Therefore, metformin may be a potential new therapy for heart failure.

The natriuretic peptides (NP) are a group of structurally similar but genetically distinct peptides with many favorable physiological properties that have emerged as important candidates for development of diagnostic tools and therapeutic agents in cardiovascular diseases. The NP family includes atrial natriuretic peptide (ANP, 28AA), urodilatin (INN: Ularitide, 32 AA), B-type natriuretic peptide (BNP, 32AA), C-type natriuretic peptide (CNP, 22AA), and D-type natriuretic peptide (DNP, 38AA). They share common features and exhibit tissue distribution of gene expression as well as functional and pharmacological characteristics. The primary sites of synthesis of the NP are the heart and brain; additional extra cardiac and extra cranial sites include intestine and kidney. Membrane-bound guanyl cyclase-coupled NP receptors (NPR) (A- and B- types) are generally implicated in mediating NP effects via the production of cyclic GMP as the intracellular messenger. NPR-C lacking the guanyl cyclase domain may influence the target cell function through inhibitory guanine nucleotide (Gi) protein, and they likely also act as clearance receptors for circulating peptides. NPs are identified as regulatory diuretic-natriuretic substances responsible for salt and water homeostasis and as hormones lowering blood pressure. This review discusses the essential biochemistry, physiological properties of NP and their manifold functional implications in cardiovascular medicine.

The hypertrophic response of the heart has been recognized recently as the net result of activation of prohypertrophic and antihypertrophic pathways. Here we report the involvement of the Wnt/Frizzled pathway in the onset of cardiac hypertrophy development. Stimulation of the Wnt/Frizzled pathway activates the disheveled (Dvl) protein. Disheveled subsequently can inhibit glycogen synthase kinase-3beta, a protein with potent antihypertrophic actions through diverse molecular mechanisms. In the Wnt/Frizzled pathway, inhibition of glycogen synthase kinase-3beta leads to an increased amount of beta-catenin, which can act as a transcription factor for several hypertrophy-associated target genes. In this study we subjected mice lacking the Dvl-1 gene and their wild-type littermates to thoracic aortic constriction for 7, 14, and 35 days. In mice lacking the Dvl-1 gene, 7 days of pressure overload-induced increases in left ventricular posterior wall thickness and expression of atrial natriuretic factor and brain natriuretic protein were attenuated compared with their wild-type littermates. Beta-catenin protein amount was reduced in the group lacking the Dvl-1 gene, and an increased glycogen synthase kinase-3beta activity was observed. Moreover, the increase in the amount of Ser(473)-phosphorylated Akt, a stimulator of cardiac hypertrophy, was lower in the group lacking the Dvl-1 gene. In conclusion, we have demonstrated that interruption of Wnt signaling in the mice lacking the Dvl-1 gene attenuates the onset of pressure overload-induced cardiac hypertrophy through mechanisms involving glycogen synthase kinase-3beta and Akt. Therefore, the Wnt/Frizzled pathway may provide novel therapeutic targets for antihypertrophic therapy.

C-type natriuretic peptide (CNP) cDNA was cloned from the tilapia brain and its inferred mature sequence was chemically synthesized together with previously cloned tilapia A-type and B-type natriuretic peptides (ANP and BNP). The cloned CNP belongs to the CNP-1 type of teleosts. Reverse-transcription polymerase chain reaction showed that the ANP and BNP genes were hardly expressed in the tilapia brain and pituitary, whereas the CNP gene was expressed strongly in the brain and slightly in the pituitary. Effects of homologous natriuretic peptides (100 nM each) on growth hormone (GH) and prolactin (PRL) release were examined using dispersed tilapia pituitary cells. Tilapia ANP and BNP stimulated GH and PRL release during 4-8, and 8-24 h of incubation. BNP appeared to be more potent than ANP, also stimulating GH and PRL release during 0-4 h of incubation. CNP stimulated GH release only during 4-8 h of incubation; CNP was without effect on PRL release. All three NPs stimulated GH and PRL mRNA expression in dispersed pituitary cells following 24 h of incubation. ANP and BNP significantly elevated intracellular cGMP accumulation in dispersed pituitary cells after 15 min of exposure, whereas no effect of CNP was observed. These results indicate a long-lasting stimulation of GH and PRL release by ANP and BNP that is mediated, at least in part, by the guanylyl cyclase-linked NP receptor.

Functional characterization of ES cell-derived cardiomyocytes is important for differentiation control and application to the cell therapy. One of the crucial functions of cardiomyocytes is a production of atrial and brain natriuretic peptides (ANP and BNP, respectively), which have important endocrine, autocrine, and paracrine functions. In this study, we focused on the functional aspect of the cardiomyocytes differentiated from monkey ES cells in vitro and investigated the expression of ANP and BNP. Spontaneously contracting cells showed nodal-like action potentials, and expression of ANP and BNP by RT-PCR and immunocytochemistry. Interestingly, ANP and BNP expressions were detected as immunoreactive granules in the perinuclear area and these signals appeared to co-localize with trans-Golgi network. These findings suggest that monkey ES cells were able to differentiate into cardiomyocytes with functional characteristics in vitro and therefore can be used as a useful model to study mechanisms and functions in early cardiogenesis.

The cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are polypeptide hormones synthesized, stored, and secreted by cardiac muscle cells (cardiocytes). The NPs modulate extracellular fluid volume and blood pressure and have potent growth-regulating properties, which make them of great interest for cardiac remodeling in acute myocardial infarction and congestive heart failure. We have observed that the production of NP can be coordinately or discoordinately regulated. In the former type, muscle stretch-elicited secretion triggers signals mediated by Gi/o protein, whereas agonists such as endothelin 1 independently signal through Gq. Discoordinated regulation is observed following stimulations by some cytokines, which selectively up-regulate BNP. This regulation takes place at the translational and transcriptional levels and is dependent on a p38 signaling pathway. Further details of processes regulating NP secretion need to be defined to develop a comprehensive view of the endocrine function of the heart. Nevertheless, translational research in the area of NPs has demonstrated the usefulness of these hormones as a marker of disease and as potential therapeutic agents. The latter application of NP is particularly attractive given that ANF and BNP possess pharmacologic actions that require polypharmacy in the treatment of acute myocardial infarction and congestive heart failure.

Homologues of the guanylin peptide family are expressed in teleost fish. Using the eel as a model euryhaline species, cDNAs for three peptides, guanylin, uroguanylin, and renoguanylin, were cloned and found to be expressed within both renal and intestinal epithelia. Seawater (SW) acclimation resulted in upregulation of uroguanylin mRNA expression in the intestinal epithelia of both immature "yellow" and sexually mature "silver" eels. SW acclimation also resulted in an increase in guanylin mRNA in silver eel intestine, whereas there was no change in renoguanylin mRNA expression under any condition. No changes in expression were found in the kidney following SW acclimation.

Pulmonary arterial hypertension (PAH) is a severe disease usually diagnosed by echocardiography and further confirmed by right heart catheterisation. Follow-up under treatment consists in assessment of clinical signs, various types of exercise testing and repeated echocardiograms. Several molecules which can be measured in the blood or sometimes in other biological fluids are known to be elevated in PAH. The most extensively studied are members of the family of natriuretic peptides, uric acid, and products generated by nitric oxide activity. Due to the low prevalence of PAH and their suboptimal specificity, these potential markers are generally of modest positive predictive value which precludes their use as screening tools. However, some of them correlate significantly with prognosis, and thus, in conjunction with classical clinical and paraclinical parameters, they may be a further aid to clinical decision-making for the specialist dealing with PAH patients.

Natriuretic peptides (NPs) have been shown to modulate neuronal activities. By immunohistochemistry and confocal microscopy, we examined expression of atrial NP (ANP), brain NP (BNP) and C-type NP (CNP) in rat retina. Our results showed that these peptides were differentially expressed in the neural retina. While strong ANP-, BNP- and CNP-immunoreactivity (IR) was clearly seen in the outer and inner plexiform layers and on numerous neurons in the inner nuclear layer, BNP- and CNP-, but not ANP-IR, was present in some ganglion cells. Furthermore, ANP, BNP and CNP were expressed in Müller cells with distinct profiles, as shown by double labeling of NPs and vimentin. Labeling for BNP was rather strong in the main trunks, major processes, but hardly detectable in the endfeet. The expression profile for ANP was similar, but with a much lower level. On the contrary, the endfeet and major processes in the inner retina were strongly CNP-positive, with the main trunks and other major processes in the outer retina much less labeled. These results raise a possibility that NPs, when released from Müller cells, may perform layer dependent functions.

The atrial natriuretic peptide (ANP)-system was examined in Rana esculenta lung with cytochemical and immunocytochemical methods. The results showed a cellular type that synthesizes the hormone and the presence of receptors in various components of the lung. The lung, therefore, produces ANP and at the same time is a target organ for the hormone. ANP may play an important physiological role in pulmonary function and in protecting against pulmonary edema., (Copyright 2004 Wiley-Liss, Inc.)

Beta-blocker therapy has been shown to be associated with an increase in the plasma concentration of A-type natriuretic peptide (ANP). Whether the plasma concentration of B-type natriuretic peptide (BNP), which is mainly derived from ventricular tissue, is also increased and whether this increase is caused by increased production or decreased metabolism by down-regulation of the natriuretic peptide-clearance receptor remains to be established. In a double-blind crossover study effects of 8 weeks' treatment of bisoprolol,10 mg once daily, and losartan, 50 mg once daily, on plasma concentrations of ANP, BNP, and N-terminal (Nt)-ANP and ambulatory blood pressure (ABP) were measured in 24 hypertensive patients. With bisoprolol plasma concentrations of ANP and BNP increased (P < 0.001) by 93 +/- 88% (mean +/- SD) and 148 +/- 117%, whereas these parameters did not change with losartan. Nt-ANP, which is not metabolized by the NP clearance receptor, increased by 83 +/- 45%, and increments in ANP and Nt-ANP were related (r =0.77, P < 0.001). The decrease in ABP was greater with bisoprolol than with losartan. Monotherapy with bisoprolol, but not with losartan, is associated with substantial increments in plasma concentrations of ANP, Nt-ANP, and BNP. As the magnitude of the increase in ANP and Nt-ANP was comparable, the beta-blocker-induced increase in NPs is not likely to be explained by a decrease in NP clearance receptor density.