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Previous work showed a role of BNIP3 in myocardial remodeling and progression to HFrEF. We utilized a multiomics approach to unravel BNIP3-related molecular mechanisms in the pathogenesis of HFrEF. BNIP3 knockdown in HFrEF improved glycolysis, pyruvate metabolism, branched-chain amino acid catabolism, and oxidative phosphorylation, and restored endoplasmic reticulum (ER)–mitochondrial (mt) calcium and ion homeostasis. These effects of BNIP3 on cardiac metabolism were related to its interaction and downregulation, and/or phosphorylation, of specific mt-proteins involved in the aforementioned metabolic pathways, including the MICOS and SLC25A families of carrier proteins. BNIP3 affected ER–mt-calcium and ion homeostasis via its interaction-induced VDAC1 dimerization and modulation of VDAC1 phosphorylation at Ser104 and Ser241, and the downregulation of LETM1. At the ER level, BNIP3 interacted with the enzyme SERCA2a and the PKA signaling complex, leading to the downregulation of SERCA2a and PKA-mediated Ser16 phospholamban phosphorylation. Additionally, BNIP3 attenuated AMPK and PRKCE activity by modulating AMPK phosphorylation at Ser485/491 and Ser377 residues, and PRKCE phosphorylation at Thr521 and Thr710 residues. BNIP3 also interacted with sarcomeric, cytoskeletal, and cellular transcription and translation proteins, and affected their expression and/or phosphorylation. In conclusion, BNIP3 modulates multiple pathobiological processes and constitutes an attractive therapeutic target in HFrEF. [ABSTRACT FROM AUTHOR]

First published August 14, 2020; doi:10.1152/ajpheart.00064.2020.--Insulin-like growth factor-1 (IGF-1) decreases atherosclerosis in apolipoprotein E (Apoe)-deficient mice when administered systemically. However, mechanisms for its atheroprotective effect are not fully understood. We generated endothelium-specific IGF-1 receptor (IGF1R)-deficient mice on an Apoe-deficient background to assess effects of IGF-1 on the endothelium in the context of hyperlipidemia-induced atherosclerosis. Endothelial deficiency of IGF1R promoted atherosclerotic burden, when animals were fed on a high-fat diet for 12 wk or normal chow for 12 mo. Under the normal chow feeding condition, the vascular relaxation response to acetylcholine was increased in the endothelial IGF1R-deficient aorta; however, feeding of a high-fat diet substantially attenuated the relaxation response, and there was no difference between endothelial IGF1R-deficient and control mice. The endothelium and its intercellular junctions provide a barrier function to the vasculature. In human aortic endothelial cells, IGF-1 upregulated occludin, claudin 5, VE-cadherin, JAM-A, and CD31 expression levels, and vice versa, specific IGF1R inhibitor, picropodophyllin, an IGF1R-neutralizing antibody (IR3), or siRNA to IGF1R abolished the IGF-1 effects on junction and adherens proteins, suggesting that IGF-1 promoted endothelial barrier function. Moreover, endothelial transwell permeability assays indicated that inhibition of IGF-1 signaling elevated solute permeability through the monolayer of human aortic endothelial cells. In summary, endothelial IGF1R deficiency increases atherosclerosis, and IGF-1 positively regulates tight junction protein and adherens junction protein levels and endothelial barrier function. Our findings suggest that the elevation of the endothelial junction protein level is, at least in part, the mechanism for antiatherogenic effects of IGF-1. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is a hallmark of cellular aging. Mitophagy is a critical mitochondrial quality control mechanism that removes dysfunctional mitochondria and contributes to cell survival. Insulin-like growth factor 1 (IGF-1) promotes survival of smooth muscle cells (SMCs), but its potential effect on cellular aging is unknown yet. We found that IGF-1 decreased cell senescence, prevented DNA telomere shortening, increased mitochondrial membrane potential, activated cytochrome C oxidase, and reduced mitochondrial DNA damage in long-term cultured (aged) aortic SMC, suggesting an antiaging effect. IGF-1 increased mitophagy in aged cells, and this was associated with decreased expression of cyclin-dependent kinase inhibitors p16 and p21 and elevated levels of Nrf2 and Sirt3, regulators of mitophagy and mitochondrial biogenesis. SiRNA-induced inhibition of either Nrf2 or Sirt3 blocked IGF-1-induced upregulation of mitophagy, suggesting that the Nrf2/Sirt3 pathway was required for IGF-1's effect on mitophagy. PINK1 is a master regulator of mitophagy. PINK1 silencing suppressed mitophagy and inhibited IGF-1-induced antiaging effects in aged SMC, consistent with an essential role of mitophagy in IGF-1's effect on cellular aging. Thus, IGF-1 inhibited cellular aging via Nrf2/Sirt3-dependent activation of mitophagy. Our data suggest that activation of IGF-1 signaling is a novel potential strategy to activate mitophagy and slow cellular aging. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II)-induced skeletal muscle wasting is characterized by activation of the ubiquitin-proteasome system. However, the potential involvement of proteolytic system macroautophagy/autophagy in this wasting process remains elusive. Autophagy is precisely regulated to maintain cell survival and homeostasis; thus its dysregulation (i.e., overactivation or persistent suppression) could lead to detrimental outcomes in skeletal muscle. Here we show that infusion of ANG II for 7 days in male FVB mice suppressed autophagy in skeletal muscle. ANG II blunted microtubule-associated protein 1 light chain 3B (LC3B)-I-to-LC3B-II conversion (an autophagosome marker), increased p62/SQSTM1 (an autophagy cargo receptor) protein expression, and decreased the number of autophagic vacuoles. ANG II inhibited UNC-51-like kinase 1 via inhibition of 5'-AMP-activated kinase and activation of mechanistic target of rapamycin complex 1, leading to reduced phosphorylation of beclin-1Ser14 and Autophagy-related protein 14Ser29, suggesting that ANG II impairs autophagosome formation in skeletal muscle. In line with ANG II-mediated suppression of autophagy, ANG II promoted accumulation of abnormal/damaged mitochondria, characterized by swelling and disorganized cristae and matrix dissolution, with associated increase in PTEN-induced kinase 1 protein expression. ANG II also reduced mitochondrial respiration, indicative of mitochondrial dysfunction. Together, these results demonstrate that ANG II reduces autophagic activity and disrupts mitochondrial ultrastructure and function, likely contributing to skeletal muscle wasting. Therefore, strategies that activate autophagy in skeletal muscle have the potential to prevent or blunt ANG II-induced skeletal muscle wasting in chronic diseases. NEW & NOTEWORTHY Our study identified a novel mechanism whereby angiotensin II (ANG II) impairs mitochondrial energy metabolism in skeletal muscle. ANG II suppressed autophagosome formation by inhibiting the UNC-51-like kinase 1(ULK1)-beclin-1 axis, resulting in accumulation of abnormal/damaged and dysfunctional mitochondria and reduced mitochondrial respiratory capacity. Therapeutic strategies that activate the ULK1-beclin-1 axis have the potential to delay or reverse skeletal muscle wasting in chronic diseases characterized by increased systemic ANG II levels. [ABSTRACT FROM AUTHOR]

Estrogen has been shown to affect vascular reactivity. Here, we assessed the estrogen receptor-α (ERα) dependency of estrogenic effects on vasorelaxation via a rapid nongenomic pathway in both male and ovary-intact female mice. We compared the effect of a primary estrogen, 17β-estradiol (E2) or 4,4',4''-(4-propyl-[1H]pyrazole-1,3,5-triyl)tris-phenol (PPT; selective ERα agonist). We found that E2 and PPT induced greater aortic relaxation in female mice than in male mice, indicating ERα mediation, which was further validated by using ERα antagonism. Treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP dihydrochloride; ERα antagonist) attenuated PPT-mediated vessel relaxation in both sexes. ERα-mediated vessel relaxation was further validated by the absence of significant PPT-mediated relaxation in aortas isolated from ERα knockout mice. Treatment with a specific ERK inhibitor, PD- 98059, reduced E2-induced vessel relaxation in both sexes but to a lesser extent in female mice. Furthermore, PD-98059 prevented PPTinduced vessel relaxation in both sexes. Both E2 and PPT treatment activated ERK as early as 5-10 min, which was attenuated by PD-98059 in aortic tissue, cultured primary vascular smooth muscle cells (VSMCs), and endothelial cells (ECs). Aortic rings denuded of endothelium showed no differences in vessel relaxation after E2 or PPT treatment, implicating a role of ECs in the observed sex differences. Here, our results are unique to show estrogen-stimulated rapid ERα signaling mediated by ERK activation in aortic tissue, as well as VSMCs and ECs in vitro, in regulating vascular function by using side-by-side comparisons in male and ovary-intact female mice in response to E2 or PPT. [ABSTRACT FROM AUTHOR]

Introduction Arterial restenosis after angioplasty/stenting has hindered coronary artery disease treatment, especially in diabetics. We theorized that gastrin-releasing peptide (GRP) antagonists and growth hormone-releasing hormone (GHRH) antagonists might decrease neointimal hyperplasia and restenosis in diabetic rats after common carotid arterial balloon injury. Methods Two separate experiments were conducted to test the effects of a GRP antagonist (RC-3095) and a GHRH antagonist (MZ-4-71) on vascular smooth muscle (VSM) growth. In a preliminary in vitro experiment non-injured human aortic vascular smooth muscle (VSM) proliferation was compared between growth media and control. In a second in vivo experiment, intimal and medial area, intima/media ratio (IM) and percent stenosis were compared between injured carotid arteries in twelve Zucker type II obese rats treated with subcutaneously injected RC-3095, MZ-4-71, or control media. Results In the in vitro experiment, decreased VSM cell growth was observed in GRP antagonist (p < 0.05) and GHRH antagonist groups (p < 0.05) compared to the control group. In the in vivo experiment, the GRP antagonist group had a decreased IM ratio (1.63 ± 0.41, p < 0.05) and an increased area of stenosis (98.78% ± 1.48 p = NS) compared to control (2.38 ± 1.09) while the GHRH antagonist group had decreased IM ratio (1.33 ± 0.58 SD, p < 0.05) and percent area of stenosis (78.84% ± 24.97, p < 0.05) compared to control (2.38 ± 1.09). Conclusions The significant decrease in both IM ratio and percent area of stenosis in the GHRH antagonist group supports the hypothesis that this peptide may reduce neointimal hyperplasia and restenosis. [ABSTRACT FROM AUTHOR]

IMPORTANCE: Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared with the general population. Prior studies have produced contradictory results on the association of dietary sodium intake with risk of CVD, and this relationship has not been investigated in patients with CKD. OBJECTIVE: To evaluate the association between urinary sodium excretion and clinical CVD events among patients with CKD. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of patients with CKD from 7 locations in the United States enrolled in the Chronic Renal Insufficiency Cohort Study and followed up from May 2003 to March 2013. EXPOSURES: The cumulative mean of urinary sodium excretion from three 24-hour urinary measurements and calibrated to sex-specific mean 24-hour urinary creatinine excretion. MAIN OUTCOMES AND MEASURES: A composite of CVD events defined as congestive heart failure, stroke, or myocardial infarction. Events were reported every 6 months and confirmed by medical record adjudication. RESULTS: Among 3757 participants (mean age, 58 years; 45% women), 804 composite CVD events (575 heart failure, 305 myocardial infarction, and 148 stroke) occurred during a median 6.8 years of follow-up. From lowest (<2894 mg/24 hours) to highest (≥4548 mg/24 hours) quartile of calibrated sodium excretion, 174, 159, 198, and 273 composite CVD events occurred, and the cumulative incidence was 18.4%, 16.5%, 20.6%, and 29.8% at median follow-up. In addition, the cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2% vs 13.3% for heart failure, 10.9% vs 7.8% for myocardial infarction, and 6.4% vs 2.7% for stroke at median follow-up. Hazard ratios of the highest quartile compared with the lowest quartile were 1.36 (95% CI, 1.09-1.70; P=.007) for composite CVD events, 1.34 (95% CI, 1.03-1.74; P=.03) for heart failure, and 1.81 (95% CI, 1.08-3.02; P=.02) for stroke after multivariable adjustment. Restricted cubic spline analyses of the association between sodium excretion and composite CVD provided no evidence of a nonlinear association (P=.11) and indicated a significant linear association (P<.001). CONCLUSIONS AND RELEVANCE: Among patients with CKD, higher urinary sodium excretion was associated with increased risk of CVD. [ABSTRACT FROM AUTHOR]

Both oxidative stress and inflammation contribute to chronic hypertension-induced myocardial fibrosis and adverse cardiac remodeling. Here we investigated whether angiotensin (Ang)-II-induced fibroblast proliferation and migration are NADPH oxidase (Nox) 4/ROS and IL-18 dependent. Our results show that the potent induction of mouse cardiac fibroblast (CF) proliferation and migration by Ang-II is markedly attenuated by Nox4 knockdown and the Nox inhibitor DPI. Further, Nox4 knockdown and DPI pre-treatment attenuated Ang-II-induced IL-18, IL-18Rα and collagen expression, and MMP9 and LOX activation. While neutralization of IL-18 blunted Ang-II-induced CF proliferation and migration, knockdown of MMP9 attenuated CF migration. The antioxidant NAC and the cell-permeable SOD mimetics Tempol, MnTBAP, and MnTMPyP attenuated oxidative stress and inhibited CF proliferation and migration. The Nox1/Nox4 dual inhibitor GKT137831 also blunted Ang-II-induced H2O2 production and CF proliferation and migration. Further, AT1 bound Nox4, and Ang-II enhanced their physical association. Notably, GKT137831 attnuated the AT1/Nox4 interaction. These results indicate that Ang-II induces CF proliferation and migration in part via Nox4/ROS-dependent IL-18 induction and MMP9 activation, and may involve AT1/Nox4 physical association. Thus, either (i) neutralizing IL-18, (ii) blocking AT1/Nox4 interaction or (iii) use of the Nox1/Nox4 inhibitor GKT137831 may have therapeutic potential in chronic hypertension-induced adverse cardiac remodeling. J. Cell. Physiol. 231: 1130-1141, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Sarcopenia and cachexia are muscle-wasting syndromes associated with aging and with many chronic diseases such as congestive heart failure, diabetes, cancer, chronic obstructive pulmonary disease, and renal failure. While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). We found that Ang II infusion in rodents leads to skeletal muscle wasting via alterations in insulin-like growth factor-1 signaling, increased apoptosis, enhanced muscle protein breakdown via the ubiquitin-proteasome system, and decreased appetite resulting from downregulation of hypothalamic orexigenic neuropeptides orexin and neuropeptide Y. Furthermore, Ang II inhibits skeletal muscle stem cell proliferation, leading to lowered muscle regenerative capacity. Distinct stem cell Ang II receptor subtypes are critical for regulation of muscle regeneration. In ischemic mouse congestive heart failure model skeletal muscle wasting and attenuated muscle regeneration are Ang II dependent. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states. [ABSTRACT FROM AUTHOR]

Prehypertension is an important phenotype for cardiovascular risk and development of established hypertension. To better understand the early circulatory changes in this group, the authors studied 34 patients with prehypertension (blood pressure 120-139/80-89 mm Hg) using digital plethysmography for measurement of blood flow and reactive hyperemic index (RHI). Arterial augmentation index (AI) was also measured. Because prehypertension is associated with endothelial dysfunction and decreased availability of nitric oxide (NO), indices of arginine metabolism (l-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, and l-citrulline) were measured. Nebivolol (5 mg/d), a vasodilating β1 -antagonist with β3 -agonist activity, was studied in a double-blind fashion for 8 weeks. Nebivolol increases the bioavailability of NO. Prehypertension was associated with normal RHI and baseline digital blood flow. AI was abnormal and associated with diastolic blood pressure. ADMA concentration was increased at baseline. After 8 weeks of nebivolol therapy, RHI, ADMA, symmetric dimethylarginine, and AI showed no significant change, but digital blood flow and l-citrulline levels were significantly increased. Prehypertension is associated with increased ADMA and evidence of increased arterial stiffness and preserved RHI. Nebivolol therapy is associated with digital vasodilation and increased NO production, as depicted by increased levels of l-citruline and mean digital blood flow. [ABSTRACT FROM AUTHOR]

Prehypertension is an important phenotype for cardiovascular risk and development of established hypertension. To better understand the early circulatory changes in this group, the authors studied 34 patients with prehypertension (blood pressure 120-139/80-89 mm Hg) using digital plethysmography for measurement of blood flow and reactive hyperemic index ( RHI). Arterial augmentation index ( AI) was also measured. Because prehypertension is associated with endothelial dysfunction and decreased availability of nitric oxide ( NO), indices of arginine metabolism ( l-arginine, asymmetric dimethylarginine ( ADMA), symmetric dimethylarginine, and l-citrulline) were measured. Nebivolol (5 mg/d), a vasodilating β1-antagonist with β3-agonist activity, was studied in a double-blind fashion for 8 weeks. Nebivolol increases the bioavailability of NO. Prehypertension was associated with normal RHI and baseline digital blood flow. AI was abnormal and associated with diastolic blood pressure. ADMA concentration was increased at baseline. After 8 weeks of nebivolol therapy, RHI, ADMA, symmetric dimethylarginine, and AI showed no significant change, but digital blood flow and l-citrulline levels were significantly increased. Prehypertension is associated with increased ADMA and evidence of increased arterial stiffness and preserved RHI. Nebivolol therapy is associated with digital vasodilation and increased NO production, as depicted by increased levels of l-citruline and mean digital blood flow. [ABSTRACT FROM AUTHOR]

The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18-induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18-induced migration of primary mouse CF was dependent on both IKK/NF-κB- and JNK/AP-1-mediated MMP9 induction and Sp1-mediated RECK suppression, mechanisms that required Nox4-dependent H2O2 generation. Notably, forced expression of RECK attenuated IL-18-induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18-induced H2O2 generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18-induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms. J. Cell. Physiol. 229: 845-855, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Metabolic remodeling plays an important role in the pathophysiology of heart failure (HF). We sought to characterize metabolic remodeling and implicated signaling pathways in two rat models of early systolic dysfunction (MOD), and overt systolic HF (SHF). Tandem mass tag-labeled shotgun proteomics, phospho-(p)-proteomics, and non-targeted metabolomics analyses were performed in left ventricular myocardium tissue from Sham, MOD, and SHF using liquid chromatography–mass spectrometry, n = 3 biological samples per group. Mitochondrial proteins were predominantly down-regulated in MOD (125) and SHF (328) vs. Sham. Of these, 82% (103/125) and 66% (218/328) were involved in metabolism and respiration. Oxidative phosphorylation, mitochondrial fatty acid β-oxidation, Krebs cycle, branched-chain amino acids, and amino acid (glutamine and tryptophan) degradation were highly enriched metabolic pathways that decreased in SHF > MOD. Glycogen and glucose degradation increased predominantly in MOD, whereas glycolysis and pyruvate metabolism decreased predominantly in SHF. PKA signaling at the endoplasmic reticulum–mt interface was attenuated in MOD, whereas overall PKA and AMPK cellular signaling were attenuated in SHF vs. Sham. In conclusion, metabolic remodeling plays an important role in myocardial remodeling. PKA and AMPK signaling crosstalk governs metabolic remodeling in progression to SHF. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF), a debilitating disease in a growing number of adults, exerts structural and neurohormonal changes in both cardiac and skeletal muscles. However, these alterations and their affected molecular pathways remain uncharacterized. Disease progression is known to transform skeletal muscle fiber composition by unknown mechanisms. In addition, perturbation of specific hormonal pathways, including those involving skeletal muscle insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-5 (IGFB-5) appears to occur, likely affecting muscle metabolism and regeneration. We hypothesized that changes in IGF-1 and IGFB-5 mRNA levels correlate with the transformation of single-skeletal muscle fiber myosin heavy chain isoforms early in disease progression, making these molecules valuable markers of skeletal muscle changes in heart failure. Materials and methods: To investigate these molecules during "early" events in HF patients, we obtained skeletal muscle biopsies from New York Heart Association (NYHA) Class II HF patients and controls for molecular analyses of single fibers, and we also quantified isometric strength and muscle size. Results: There were more (P < 0.05) single muscle fibers coexpressing two or more myosin heavy chains in the HF patients (30% ± 7%) compared to the control subjects (13% ± 2%). IGF-1 and IGFBP-5 expression was fivefold and 15-fold lower in patients with in HF compared to control subjects (P < 0.05), respectively. Strikingly, there was a correlation in IGF-1 expression and muscle cross-sectional area (P < 0.05) resulting in a decrease in whole-muscle quality (P < 0.05) in the HF patients, despite no significant decrease in isometric strength or whole-muscle size. Conclusion: These data indicate that molecular alterations in myosin heavy chain isoforms, IGF-1, and IGFB-5 levels precede the gross morphological and functional deficits that have previously been associated with HF, and may be used as a predictor of functional outcome in patients. [ABSTRACT FROM AUTHOR]

The redox- sensitive transcription factors NF-κB and activator protein-1 (AP-1) are critical mediators of ANG II signaling. The promitogenic and promigratory factor interleukin (IL)-18 is an NF-κB- and AP-1- responsive gene. Therefore, we investigated whether ANG II-mediated smooth muscle cell (SMC) migration and proliferation involve IL-18. ANG II induced rat carotid artery SMC migration and proliferation and IL-18 and metalloproteinase (MMP)-9 expression via ANG II type 1 (AT1) receptor. ANG II-induced superoxide generation, NF-κB and AP-1 activation, and IL-18 and MMP-9 induction were all markedly attenuated by losartan, diphenyleneiodonium chloride (DPI), and Nox1 knockdown. Similar to ANG II, addition of IL-18 also induced superoxide generation, activated NF-κB and AP-1, and stimulated SMC migration and proliferation, in part via Nox1, and both ANG II and IL-18 induced NOX1 transcription in an AP-1- dependent manner. AT1 physically associates with Nox1 in SMC, and ANG II enhanced this binding. Interestingly, exogenous IL-18 neither induced AT1 binding to Nox1 nor enhanced the ANG II-induced increase in AT1/Nox1 binding. Importantly, IL-18 knockdown, or pretreatment with IL-18 neutralizing antibodies, or IL-18 binding protein, all attenuated the migratory and mitogenic effects of ANG II. Continuous infusion of ANG II for 7 days induced carotid artery hyperplasia in rats via AT1 and was associated with increased AT1/ Nox1 binding (despite lower AT1 levels); increased DPI-inhibitable superoxide production; increased phospho-IKKβ, JNK, p65, and c- Jun; and induction of IL-18 and MMP-9 in endothelium-denuded carotid arteries. These results indicate that IL-18 amplifies the ANG II-induced, redox-dependent inflammatory cascades by activating similar promitogenic and promigratory signal transduction pathways. The ANG II/Nox1/IL-18 pathway may be critical in hyperplastic vascular diseases, including atherosclerosis and restenosis. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1–induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging. [ABSTRACT FROM PUBLISHER]

Advanced congestive heart failure (CHF) and chronic kidney disease (CKD) are characterized by increased angiotensin II (Ang II) levels and are often accompanied by significant skeletal muscle wasting that negatively impacts mortality and morbidity. Both CHF and CKD patients have respiratory muscle dysfunction, however the potential effects of Ang II on respiratory muscles are unknown. We investigated the effects of Ang II on diaphragm muscle in FVB mice. Ang II induced significant diaphragm muscle wasting (18.7±1.6% decrease in weight at one week) and reduction in fiber cross-sectional area. Expression of the E3 ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) and of the pro-apoptotic factor BAX was increased after 24 h of Ang II infusion (4.4±0.3 fold, 3.1±0.5 fold and 1.6±0.2 fold, respectively, compared to sham infused control) suggesting increased muscle protein degradation and apoptosis. In Ang II infused animals, there was significant regeneration of injured diaphragm muscles at 7 days as indicated by an increase in the number of myofibers with centralized nuclei and high expression of embryonic myosin heavy chain (E-MyHC, 11.2±3.3 fold increase) and of the satellite cell marker M-cadherin (59.2622.2% increase). Furthermore, there was an increase in expression of insulin-like growth factor-1 (IGF-1, 1.8±0.3 fold increase) in Ang II infused diaphragm, suggesting the involvement of IGF-1 in diaphragm muscle regeneration. Bone-marrow transplantation experiments indicated that although there was recruitment of bone-marrow derived cells to the injured diaphragm in Ang II infused mice (267.0±74.6% increase), those cells did not express markers of muscle stem cells or regenerating myofibers. In conclusion, Ang II causes marked diaphragm muscle wasting, which may be important for the pathophysiology of respiratory muscle dysfunction and cachexia in conditions such as CHF and CKD. [ABSTRACT FROM AUTHOR]

We demonstrate for the first time that the pro-inflammatory cytokine interleukin (IL)-18 stimulates rapid and significant proliferation of SMC derived from human saphenous vein (VSMC), but not coronary artery. IL-18 also stimulates VSMC growth. Further investigations revealed that IL-18-induced VSMC proliferation was Wnt inducible secreted protein-1 (WISP1) dependent. In addition to inducing its own expression via phosphatidylinositol 3-kinase/Akt-dependent IKK/NF-κB activation, IL-18 stimulated glycogen synthase kinase 3β phosphorylation and degradation, β-catenin nuclear translocation and stabilization, T-cell factor-lymphoid enhancer binding factor (TCF-LEF) activation, and WISP1 induction. Moreover, WISP1 induced its own expression, and that of survivin and multiple matrix metalloproteinases via β-catenin/TCF-LEF interaction. WISP1 also activated AP-1, but not NF-κB, and induced matrix metalloproteinase ( MMP)9 transcription in part via AP-1. Interestingly, WISP1 failed to regulate tissue inhibitors of matrix metalloproteinases (TIMP) expression. These novel findings indicate that IL-18 induces a series of signaling events that result in WISP1-mediated VSMC proliferation, survival and MMP induction that are key components of vein graft stenosis and this may be amplified by IL-18 and WISP1 autoregulation and cross-regulation. J. Cell. Physiol. 226: 3303-3315, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Some clinical studies have suggested that lower IGF-I levels may be associated with an increased risk of ischemic heart disease. We generated atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice with 6T alleles (6T/ApoE-/- mice) with a 20% decline in circulating IGF-I and fed these mice and control ApoE-/- mice with normal chow or a Western diet for 12 wk to evaluate the effect of low serum IGF-I on atherosclerosis progression. We found that the 6T/ApoE-/- phenotype was characterized by an increased atherosclerotic burden, elevated plaque macrophages, and increased proinflammatory cytokine TNF-α levels compared with ApoE-/- controls. 6T/ApoE-/- mice had similar body weight, blood pressure, serum total cholesterol levels, total plaque and smooth muscle cell apoptosis rates, and circulating levels of endothelial progenitor cells as ApoE-/- mice. 6T/ApoE-/- mice fed with normal chow had reduced vascular endothelial nitric oxide synthase mRNA levels and a trend to increased aortic expression of chemokine (C-C motif) receptor (CCR)1, CCR2, and monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 2. Western diet-fed 6T/ApoE-/- mice had a trend to increased expression of macrophage scavenger receptor-1/scavenger receptor-A, osteopontin, ATP-binding cassette (subfamily A, member 1), and angiotensin-converting enzyme and elevated circulating levels of the neutrophil chemoattractant chemokine (C-X-C motif) ligand 1 (KC). Our data establish a link between lower circulating IGF-I and increased atherosclerosis that has important clinical implications. [ABSTRACT FROM AUTHOR]

Congestive heart failure is associated with activation of the reninangiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atroginI and muscle ring finger-I (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atroginI and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atroginI, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG IImediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Aktand Foxo1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRFI expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG 11-induced wasting in vivo. [ABSTRACT FROM AUTHOR]

Oxidized low-density lipoprotein (LDL) is proatherogenic and induces smooth muscle cell apoptosis, which contributes to atherosclerotic plaque destabilization. We showed previously that oxidized LDL downregulates insulin-like growth factor-1 receptor in human smooth muscle cells and that this is critical for induction of apoptosis. To identify mechanisms, we exposed smooth muscle cells to 60 µg/ml oxidized LDL or native LDL and assessed insulin-like growth factor-1 receptor mRNA levels, protein synthesis rate, and receptor protein stability. Oxidized LDL decreased insulin-like growth factor-1 receptor mRNA levels by 30% at 8 h compared with native LDL, and this decrease was maintained for up to 20 h. However, insulin-like growth factor-1 receptor protein synthesis rate was not altered by oxidized LDL. Pulse-chase labeling experiments revealed that oxidized LDL reduced insulin-like growth factor-1 receptor protein half-life to 12.2 ± 1.7 h from 24.4 ± 4.7 h with native LDL. This destabilization of insulin-like growth factor-1 receptor protein was accompanied by enhanced receptor ubiquitination. Overexpression of dominant-negative Nedd4 prevented oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor, suggesting that Nedd4 was the ubiquitin ligase that mediated receptor downregulation. However, the proteasome inhibitors lactacystin, MG-132, and proteasome inhibitor-1 failed to block oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor. Thus oxidized LDL downregulates insulin-like growth factor-1 receptor by destabilizing the protein via Nedd4- enhanced ubiquitination, leading to degradation via a proteasome-independent pathway. This finding provides novel insights into oxidized LDL-triggered oxidant signaling and mechanisms of smooth muscle cell depletion that contribute to plaque destabilization and coronary events. [ABSTRACT FROM AUTHOR]

(ECHOCARDIOGRAPHY, Volume 21, July 2004) [ABSTRACT FROM AUTHOR]

Background: Vessel wall responses to percutaneous transluminal coronary angioplasty include neointimal proliferation and arterial remodeling. The contraction of a collagen gel is a good in vitro model of wound repair and vascular remodeling. Because irradiation is an important new therapeutic modality capable of preventing restenosis, the purpose of this study was to evaluate the effect of irradiation on the contraction of a collagen gel by smooth muscle cells (SMCs), on SMCs viability, and on DNA synthesis.Methods: We studied the effect of different doses of gamma-irradiation (0 [control], 6, 12, and 18 Gy) on the contraction of a collagen gel seeded with SMCs (calf carotid arteries) during a period of 15 days.Results: Maximal gel diameter reduction (from 35 to 6.8 mm, +/-0.5 mm in control) was markedly inhibited in the 6-, 12-, and 18-Gy groups (35 to 13.7 mm, +/-0.8 mm; 35 to 15.5 mm, +/-0.9 mm; and 35 to 16.1 mm, +/-0.9 mm, respectively; P<0.0001). The irradiated gels showed a dose-dependent reduction in the SMC proliferation rate (P<0.0001) and an increase in the number of nonviable SMCs (P<0.002) 15 days after irradiation.Conclusions: Gamma-irradiation produces a significant dose-dependent inhibition of the contraction of collagen gels seeded with arterial SMCs. This effect is related to a significant decrease in SMC viability and a decrease in SMC proliferation rate. These findings shed light on mechanisms whereby irradiation may positively affect arterial remodeling after percutaneous transluminal coronary angioplasties. [ABSTRACT FROM AUTHOR]

The mitochondria are mostly abundant in the heart, a beating organ of high- energy demands. Their function extends beyond being a power plant of the cell including redox balance, ion homeostasis and metabolism. They are dynamic organelles that are tethered to neighboring structures, especially the endoplasmic reticulum. Together, they constitute a functional unit implicated in complex physiological and pathophysiological processes. Their topology in the cell, the cardiac myocyte in particular, places them at the hub of signaling and calcium homeostasis, making them master regulators of cell survival or cell death. Perturbations in mitochondrial function play a central role in the pathophysiology of myocardial remodeling and progression of heart failure. In this minireview, we summarize important pathophysiological mechanisms, pertaining to mitochondrial morphology, dynamics and function, which take place in compensated hypertrophy and in progression to overt systolic heart failure. Published work in the last few years has expanded our understanding of these important mechanisms; a key prerequisite to identifying therapeutic strategies targeting mitochondrial dysfunction in heart failure. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) is a key growth factor that regulates both anabolic and catabolic pathways in skeletal muscle. IGF-1 increases skeletal muscle protein synthesis via PI3K/Akt/mTOR and PI3K/Akt/GSK3β pathways. PI3K/Akt can also inhibit FoxOs and suppress transcription of E3 ubiquitin ligases that regulate ubiquitin proteasome system (UPS)-mediated protein degradation. Autophagy is likely inhibited by IGF-1 via mTOR and FoxO signaling, although the contribution of autophagy regulation in IGF-1-mediated inhibition of skeletal muscle atrophy remains to be determined. Evidence has suggested that IGF-1/Akt can inhibit muscle atrophy-inducing cytokine and myostatin signaling via inhibition of the NF-κΒ and Smad pathways, respectively. Several miRNAs have been found to regulate IGF-1 signaling in skeletal muscle, and these miRs are likely regulated in different pathological conditions and contribute to the development of muscle atrophy. IGF-1 also potentiates skeletal muscle regeneration via activation of skeletal muscle stem (satellite) cells, which may contribute to muscle hypertrophy and/or inhibit atrophy. Importantly, IGF-1 levels and IGF-1R downstream signaling are suppressed in many chronic disease conditions and likely result in muscle atrophy via the combined effects of altered protein synthesis, UPS activity, autophagy, and muscle regeneration. [ABSTRACT FROM AUTHOR]