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Background: Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A4 (LXA4), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought. Thus, we aimed to determine whether LXA4 therapeutic treatment attenuates diabetes-induced cardiac pathology. Methods: Six-week-old male apolipoprotein E-deficient (ApoE−/−) mice were followed for 16 weeks after injection of streptozotocin (STZ, 55 mg/kg/day, i.p. for 5 days) to induce type-1 diabetes (T1DM). Treatment with LXA4 (5 μg/kg, i.p.) or vehicle (0.02% ethanol, i.p.) was administered twice weekly for the final 6 weeks. One week before endpoint, echocardiography was performed within a subset of mice from each group. At the end of the study, mice were euthanized with sodium pentobarbital (100 mg/kg i.p.) and hearts were collected for ex vivo analysis, including histological assessment, gene expression profiling by real-time PCR and protein level measurement by western blot. Results: As expected diabetic mice showed a significant elevation in plasma glycated hemoglobin (HbA1c) and glucose levels, along with reduced body weight. Vehicle-treated diabetic mice exhibited increased cardiac inflammation, macrophage content, and an elevated ratio of M1-like to M2-like macrophage markers. In addition, myocardial fibrosis, cardiomyocytes apoptosis and hypertrophy (at the genetic level) were evident, with echocardiography revealing early signs of left ventricular (LV) diastolic dysfunction. Treatment with LXA4 ameliorated diabetes-induced cardiac inflammation, pro-inflammatory macrophage polarization and cardiac remodeling (especially myocardial fibrosis and cardiomyocytes apoptosis), with ultimate improvement in cardiac function. Of note, this improvement was independent of glucose control. Conclusions: These findings demonstrated that LXA4 treatment attenuated the extent of cardiac inflammation in diabetic hearts, resulting in limited cardiac remodeling and improved LV diastolic function. This supports further exploration of LXA4-based therapy for the management of diabetic heart disease. The recent development of stable LXA4 mimetics holds potential as a novel strategy to treat cardiac dysfunction in diabetes, paving the way for innovative and more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Cardiorenal fibrosis is a common feature of chronic cardiovascular disease and recent data suggests that cytokines and chemokines may also drive fibrosis. Here we tested the hypothesis that CXCR7, a highly conserved chemokine receptor, contributes to cardiac and renal fibrosis. We generated an anti-mouse CXCR7-specific monoclonal antibody (CXCR7 mAb) and tested its anti-fibrotic actions in cardiorenal fibrosis induced using the deoxycorticosterone acetate/uni-nephrectomy (DOCA-UNX) model. CXCR7 mAb treatment (10 mg/kg, twice weekly for 6 weeks) significantly attenuated the development of cardiac and renal fibrosis, and reduced fibrotic and inflammatory gene expression levels, in the absence of an effect on blood pressure. Immunohistochemical analysis demonstrated an increase in the vascular expression of CXCR7 in DOCA-UNX-treated mice. This study demonstrated that a CXCR7 mediated pathway plays a significant role in cardiac and renal fibrosis induced by DOCA-UNX treatment. Accordingly, antagonism of CXCR7 may provide a therapeutic opportunity to mitigate against fibrosis in the setting of mineralocorticoid excess. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) remains challenging to prevent and treat. A key feature of AF is atrial enlargement. However, not all atrial enlargement progresses to AF. Atrial enlargement in response to physiological stimuli such as exercise is typically benign and reversible. Understanding the differences in atrial function and molecular profile underpinning pathological and physiological atrial remodelling will be critical for identifying new strategies for AF. The discovery of molecular mechanisms responsible for pathological and physiological ventricular hypertrophy has uncovered new drug targets for heart failure. Studies in the atria have been limited in comparison. Here, we characterised mouse atria from (1) a pathological model (cardiomyocyte-specific transgenic (Tg) that develops dilated cardiomyopathy [DCM] and AF due to reduced protective signalling [PI3K]; DCM-dnPI3K), and (2) a physiological model (cardiomyocyte-specific Tg with an enlarged heart due to increased insulin-like growth factor 1 receptor; IGF1R). Both models presented with an increase in atrial mass, but displayed distinct functional, cellular, histological and molecular phenotypes. Atrial enlargement in the DCM-dnPI3K Tg, but not IGF1R Tg, was associated with atrial dysfunction, fibrosis and a heart failure gene expression pattern. Atrial proteomics identified protein networks related to cardiac contractility, sarcomere assembly, metabolism, mitochondria, and extracellular matrix which were differentially regulated in the models; many co-identified in atrial proteomics data sets from human AF. In summary, physiological and pathological atrial enlargement are associated with distinct features, and the proteomic dataset provides a resource to study potential new regulators of atrial biology and function, drug targets and biomarkers for AF. [ABSTRACT FROM AUTHOR]

Aims Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.e. hypertension-induced end-organ damage. The parallels between the murine and human hypertensive proteome were also investigated. Methods and results The hypertensive response to angiotensin II (Ang II, 0.7 mg/kg/day, s.c.) was attenuated by Cmpd17b (50 mg/kg/day, i.p.). Impairments in cardiac and vascular function assessed via echocardiography were improved by Cmpd17b in hypertensive mice. This functional improvement was accompanied by reduced cardiac and aortic fibrosis and vascular calcification. Cmpd17b also attenuated Ang II-induced increased cardiac mitochondrial complex 2 respiration. Proteomic profiling of cardiac and aortic tissues and cells, using label-free nano-liquid chromatography with high-sensitivity mass spectrometry, detected and quantified ∼6000 proteins. We report hypertension-impacted protein clusters associated with dysregulation of inflammatory, mitochondrial, and calcium responses, as well as modified networks associated with cardiovascular remodelling, contractility, and structural/cytoskeletal organization. Cmpd17b attenuated hypertension-induced dysregulation of multiple proteins in mice, and of these, ∼110 proteins were identified as similarly dysregulated in humans suffering from adverse aortic remodelling and cardiac hypertrophy. Conclusion We have demonstrated, for the first time, that the FPR agonist Cmpd17b powerfully limits hypertension-induced end-organ damage, consistent with proteome networks, supporting development of pro-resolution FPR-based therapeutics for treatment of systemic hypertension complications. [ABSTRACT FROM AUTHOR]

MicroRNA 34a (miR-34a) is elevated in the heart in a setting of cardiac stress or pathology, and we previously reported that inhibition of miR-34a in vivo provided protection in a setting of pressure overload-induced pathological cardiac hypertrophy and dilated cardiomyopathy. Prior work had also shown that circulating or cardiac miR-34a was elevated in a setting of diabetes. However, the therapeutic potential of inhibiting miR-34a in vivo in the diabetic heart had not been assessed. In the current study, type 1 diabetes was induced in adult male mice with 5 daily injections of streptozotocin (STZ). At 8 weeks post-STZ, when mice had established type 1 diabetes and diastolic dysfunction, mice were administered locked nucleic acid (LNA)-antimiR-34a or saline-control with an eight-week follow-up. Cardiac function, cardiac morphology, cardiac fibrosis, capillary density and gene expression were assessed. Diabetic mice presented with high blood glucose, elevated liver and kidney weights, diastolic dysfunction, mild cardiac enlargement, cardiac fibrosis and reduced myocardial capillary density. miR-34a was elevated in the heart of diabetic mice in comparison to non-diabetic mice. Inhibition of miR-34a had no significant effect on diastolic function or atrial enlargement, but had a mild effect on preventing an elevation in cardiac enlargement, fibrosis and ventricular gene expression of B-type natriuretic peptide (BNP) and the anti-angiogenic miRNA (miR-92a). A miR-34a target, vinculin, was inversely correlated with miR-34a expression, but other miR-34a targets were unchanged. In summary, inhibition of miR-34a provided limited protection in a mouse model with established type 1 diabetes-induced cardiomyopathy and failed to improve diastolic function. Given diabetes represents a systemic disorder with numerous miRNAs dysregulated in the diabetic heart, as well as other organs, strategies targeting multiple miRNAs and/or earlier intervention is likely to be required. [ABSTRACT FROM AUTHOR]

Myocardial fibrosis is a key histopathological component that drives the progression of heart disease leading to heart failure and constitutes a therapeutic target. Recent preclinical and clinical studies have implicated galectin-3 (Gal-3) as a pro-fibrotic molecule and a biomarker of heart disease and fibrosis. However, our knowledge is poor on the mechanism(s) that determine the blood level or regulate cardiac expression of Gal-3. Recent studies have demonstrated that enhanced β-adrenoceptor activity is a determinant of both circulating concentration and cardiac expression of Gal-3. Pharmacological or transgenic activation of β-adrenoceptors leads to increased blood levels of Gal-3 and up-regulated cardiac Gal-3 expression, effect that can be reversed with the use of β-adrenoceptor antagonists. Conversely, Gal-3 gene deletion confers protection against isoprenaline-induced cardiotoxicity and fibrogenesis. At the transcription level, β-adrenoceptor stimulation activates cardiac mammalian sterile-20-like kinase 1, a pivotal kinase of the Hippo signalling pathway, which is associated with Gal-3 up-regulation. Recent studies have suggested a role for the β-adrenoceptor-Hippo signalling pathway in the regulation of cardiac Gal-3 expression thereby contributing to the onset and progression of heart disease. This implies a therapeutic potential of the suppression of Gal-3 expression. In this review, we discuss the effects of β-adrenoceptor activity on Gal-3 as a biomarker and causative mediator in the setting of heart disease and point out pivotal knowledge gaps. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc. [ABSTRACT FROM AUTHOR]

The anti-inflammatory, pro-resolving annexin-A1 protein acts as an endogenous brake against exaggerated cardiac necrosis, inflammation, and fibrosis following myocardial infarction (MI) in vivo. Little is known, however, regarding the cardioprotective actions of the N-terminal-derived peptide of annexin A1, Ac2-26, particularly beyond its anti-necrotic actions in the first few hours after an ischemic insult. In this study, we tested the hypothesis that exogenous Ac2-26 limits cardiac injury in vitro and in vivo. Firstly, we demonstrated that Ac2-26 limits cardiomyocyte death both in vitro and in mice subjected to ischemia-reperfusion (I-R) injury in vivo (Ac2-26, 1 mg/kg, i.v. just prior to post-ischemic reperfusion). Further, Ac2-26 (1 mg/kg i.v.) reduced cardiac inflammation (after 48 h reperfusion), as well as both cardiac fibrosis and apoptosis (after 7-days reperfusion). Lastly, we investigated whether Ac2-26 preserved cardiac function after MI. Ac2-26 (1 mg/kg/day s.c., osmotic pump) delayed early cardiac dysfunction 1 week post MI, but elicited no further improvement 4 weeks after MI. Taken together, our data demonstrate the first evidence that Ac2-26 not only preserves cardiomyocyte survival in vitro , but also offers cardioprotection beyond the first few hours after an ischemic insult in vivo. Annexin-A1 mimetics thus represent a potential new therapy to improve cardiac outcomes after MI. [ABSTRACT FROM AUTHOR]

Background: Myocardial fibrosis is a key pathologic finding in the failing heart and is implicated as a cause of increased ventricular stiffness and susceptibility to ventricular arrhythmia. Neurohormonal mediators such as aldosterone and angiotensin II are known to cause fibrosis in experimental models, however, clinical evidence for the reversal of fibrosis with relevant antagonists is limited. Recent studies suggest that inflammatory mediators may contribute to fibrosis. In dilated cardiomyopathy the mechanism for myocardial fibrosis is unclear and its implications on systolic function are not known. Methods and Results: We studied the effect of a highly selective antagonist of SDF-1/CXCR4 signaling, AMD3100, on the development of cardiac fibrosis and cardiac function in mice with dilated cardiomyopathy due to cardiac-specific transgenic overexpression of the stress-kinase, Mst1. AMD3100 significantly attenuated the progression of myocardial fibrosis and this was accompanied by significant improvements in diastolic and systolic performance as evaluated in isolated Langendorff perfused hearts. AMD3100 reduced BNP mRNA expression but did not alter the expression of Ca2+ handling genes. CXCR4 antagonism also reduced the abundance of splenic CD4+ T cells. Conclusion: This study demonstrates that CXCR4 pathway contributes to pathogenesis of cardiac fibrosis in dilated cardiomyopathy, and it represents a new potential therapeutic target in heart failure. The data also demonstrate that anti-fibrotic strategies can improve systolic performance. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a central role in the pathogenesis of heart failure. We aimed to determine whether the antioxidant N-acetylcysteine can attenuate cardiac fibrosis and remodeling in a mouse model of heart failure. Minipumps were implanted subcutaneously in wild-type mice ( n = 20) and mice with cardiomyopathy secondary to cardiac specific overexpression of mammalian sterile 20-like kinase 1 ( MST-1; n = 18) to administer N-acetylcysteine (40 mg/kg per day) or saline for a period of 8 weeks. At the end of this period, cardiac remodeling and function was assessed via echocardiography. Fibrosis, oxidative stress, and expression of collagen types I and III were quantified in heart tissues. Cardiac perivascular and interstitial fibrosis were greater by 114% and 209%, respectively, in MST-1 compared to wild type ( P ≤ 0.001). In MST-1 mice administered N-acetylcysteine, perivascular and interstitial fibrosis were 40% and 57% less, respectively, compared to those treated with saline ( P ≤ 0. 03). Cardiac oxidative stress was 119% greater in MST-1 than in wild type ( P < 0.001) and N-acetylcysteine attenuated oxidative stress in MST-1 by 42% ( P = 0.005). These data indicate that N-acetylcysteine can blunt cardiac fibrosis and related remodeling in the setting of heart failure potentially by reducing oxidative stress. This study provides the basis to investigate the role of N-acetylcysteine in chronic heart failure. [ABSTRACT FROM AUTHOR]

MicroRNAs are dysregulated in a setting of heart disease and have emerged as promising therapeutic targets. MicroRNA-34 family members (miR-34a, -34b, and -34c) are up-regulated in the heart in response to stress. In this study, we assessed whether inhibition of the miR-34 family using an s.c.-delivered seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiR (LNA-antimiR-34) can provide therapeutic benefit in mice with preexisting pathological cardiac remodeling and dysfunction due to myocardial infarction (Ml) or pressure overload via transverse aortic constriction (TAC). An additional cohort of mice subjected to Ml was given LNA-antimiR-34a (15-mer) to inhibit miR-34a alone as a comparison for LNA-antimiR-34. LNA-antimiR-34 (8-mer) efficiently silenced all three miR-34 family members in both cardiac stress models and attenuated cardiac remodeling and atrial enlargement. In contrast, inhibition of miR-34a alone with LNA-antimiR-34a (15-mer) provided no benefit in the Ml model. In mice subjected to pressure overload, LNA-antimiR-34 improved systolic function and attenuated lung congestion, associated with reduced cardiac fibrosis, increased angiogenesis, increased Akt activity, decreased atrial natriuretic peptide gene expression, and maintenance of sarcoplasmic reticulum Ca2+ ATPase gene expression. Improved outcome in LNA-antimiR-34-treated Ml and TAC mice was accompanied by upregulation of several direct miR-34 targets, including vascular endothelial growth factors, vinculin, protein O-fucosyltranferase 1, Notchl, and semaphorin 4B. Our results provide evidence that silencing of the entire miR-34 family can protect the heart against pathological cardiac remodeling and improve function. Furthermore, these data underscore the utility of seed-targeting 8-mer LNA-antimiRs in the development of new therapeutic approaches for pharmacologic inhibition of diseaseimplicated miRNA seed families. [ABSTRACT FROM AUTHOR]

The article focuses on reduction capability of CXCR4 antagonist on mineralocorticoid excess' cardiorenal consequences. The study done by the authors centered on the effect of CXCR4 antagonist AMD3465 in mice treated with dexoycorticosterone acetate (DOCA). They found that there was significant reduction in the risk of cardiac fibrosis, renal fibrosis, hypertension and left ventricular hypertrophy. The authors conclude that this finding can be a new basis for cardiovascular disease treatment.

As a hallmark of heart disease, cardiac fibrosis contributes to the development of heart failure and arrhythmias and forms a key therapeutic target. There is a major unmet need for selective, potent, and safe antifibrotic drugs. Earlier studies revealed a cardiac fibrosis phenotype in relaxin-1-deficient mice. Recent studies in several rodent models of cardiac fibrosis have documented reversal of fibrosis by treatment with relaxin peptide or virally mediated relaxin gene delivery. In mice with surgically induced transmural myocardial infarction, relaxin therapy inhibited scar density. In these studies, however, functional benefits achieved by relaxin therapy were limited or less explored. Collectively, there is good experimental evidence that relaxin is able to reverse cardiac fibrosis due to distinct mechanisms. Future research needs to explore functional improvement following fibrosis reversal by relaxin and the usefulness of relaxin in antiarrhythmic or stem cell-based therapy. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is associated with most forms of cardiovascular disease. No reliable therapies targeting cardiac fibrosis are available, thus identifying novel drugs that can resolve or prevent fibrosis is needed. Tilorone, an antiviral agent, can prevent fibrosis in a mouse model of lung disease. We investigated the anti-fibrotic effects of tilorone in human cardiac fibroblasts in vitro by performing a radioisotopic assay for [3H]-proline incorporation as a proxy for collagen synthesis. Exploratory studies in human cardiac fibroblasts treated with tilorone (10 µM) showed a significant reduction in transforming growth factor-β induced collagen synthesis compared to untreated fibroblasts. To determine if this finding could be recapitulated in vivo, mice with established pathological remodelling due to four weeks of transverse aortic constriction (TAC) were administered tilorone (50 mg/kg, i.p) or saline every third day for eight weeks. Treatment with tilorone was associated with attenuation of fibrosis (assessed by Masson's trichrome stain), a favourable cardiac gene expression profile and no further deterioration of cardiac systolic function determined by echocardiography compared to saline treated TAC mice. These data demonstrate that tilorone has anti-fibrotic actions in human cardiac fibroblasts and the adult mouse heart, and represents a potential novel therapy to treat fibrosis associated with heart failure. [ABSTRACT FROM AUTHOR]