A-kinase anchoring proteins that regulate cardiac remodeling

In response to injury or stress, the adult heart undergoes maladaptive changes, collectively defined as pathological cardiac remodeling. Here, we focus on the role of A-kinase anchoring proteins (AKAPs) in 3 main areas associated with cardiac remodeling and the progression of heart failure: excitation-contraction coupling, sarcomeric regulation, and induction of pathological hypertrophy. AKAPs are a diverse family of scaffold proteins that form multiprotein complexes, integrating cAMP signaling with protein kinases, phosphatases, and other effector proteins. Many AKAPs have been characterized in the heart, where they play a critical role in modulating cardiac function.     

Deep sea minerals prolong life span of streptozotocin‐induced diabetic rats by compensatory augmentation of the IGF‐I‐survival signaling and inhibition of apoptosis

Consumption of deep sea minerals (DSM), such as magnesium, calcium, and potassium, is known to reduce hypercholesterolemia‐induced myocardial hypertrophy and cardiac‐apoptosis and provide protection against cardiovascular diseases. Heart diseases develop as a lethal complication among diabetic patients usually due to hyperglycemia‐induced cardiac‐apoptosis that causes severe cardiac‐damages, heart failure, and reduced life expectancy. In this study, we investigated the potential of DSM and its related cardio‐protection to increase the life expectancy in diabetic rats. In this study, a heart failure rat model was developed by using streptozotocin (65 mg kg^?1) IP injection. Different doses of DSM‐1× (37 mg kg^?1 day^?1), 2× (74 mg kg^?1 day^?1) and 3× (111 mg kg^?1 day^?1), were administered to the rats through gavages for 4 weeks. The positive effects of DSM on the survival rate of diabetes rats were determined with respect to the corresponding effects of MgSO₄. Further, to understand the mechanism by which DSM enhances the survival of diabetic rats, their potential to regulate cardiac‐apoptosis and control cardiac‐dysfunction were examined. Echocardiogram, tissue staining, TUNEL assay, and Western blotting assay were used to investigate modulations in the myocardial contractile function and related signaling protein expression. The results showed that DSM regulate apoptosis and complement the cardiomyocyte proliferation by enhancing survival mechanisms. Moreover DSM significantly reduced the mortality rate and enhanced the survival rate of diabetic rats. Experimental results show that DSM administration can be an effective strategy to improve the life expectancy of diabetic subjects by improving cardiac‐cell proliferation and by controlling cardiac‐apoptosis and associated cardiac‐dysfunction. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 769–781, 2016.     

Unmasking the janus faces of autophagy in obesity-associated insulin resistance and cardiac dysfunction

Autophagy is an intracellular, lysosomal-dependent process involved in the turnover of long-lived proteins, damaged organelles and other subcellular structures. The autophagic process is known to play an essential role in the maintenance of cellular homeostasis. Results from recent studies also indicate an important role for the autophagic process in the pathogenesis of human diseases, including cancer, cardiovascular diseases, obesity, diabetes mellitus and ageing. Because of the pivotal role of autophagy in the regulation of adipogenesis, obesity and insulin sensitization, research efforts have focused on elucidating the role of autophagy in metabolic syndrome. Mammalian target of rapamycin (mTOR) is a key regulator of cell growth and is characterized by a complex signalling mechanism that affects protein synthesis and autophagy. Results from experimental and clinical studies reveal some interesting, but conflicting, findings regarding the mTOR signalling pathway and autophagy in adipocytes in metabolic syndrome. Although the pivotal role of autophagy in obesity and other metabolic diseases has been established, its involvement in obesity-induced cardiac dysfunction remains unknown, as do the upstream signalling regulators of autophagy. The present minireview discusses the molecular mechanisms of autophagy in the regulation of cardiac function in overweight and obesity. Further studies using appropriate models are needed to better unravel the complex intracellular mechanisms involved in the regulation of autophagy in obesity-induced cardiac dysfunction.     

The sarcomeric cytoskeleton as a target for pharmacological intervention

Many diseases of heart and skeletal muscle, from heart failure to muscle atrophy, pose unmet needs for specific and effective treatments. Recent advances suggest that sarcomeres, the smallest contractile units of heart and skeletal muscles, can be viable pharmacological targets. In sarcomeres, the contractile actin and myosin filaments are organised by a network of proteins combining structural and signalling functions, forming the sarcomeric cytoskeleton. This includes the giant proteins titin, obscurin and nebulin, which contain protein-binding sites along with signalling domains such as protein kinase, Rho activator, and Src-homology domains. These signalling domains have recently been implicated in sarcomere assembly, and the regulation of muscle contractile and metabolic adaptation. Although many functions of sarcomeric proteins remain to be discovered, their potential as pharmacological targets is now emerging. Here, we will review recent insight into the physiological and pathological signalling functions of sarcomeric cytoskeletal proteins and discuss new aspects and strategies in skeletal muscle signalling, pathomechanisms and therapy.     

Puerarin pretreatment attenuates cardiomyocyte apoptosis induced by coronary microembolization in rats by activating the PI3K/Akt/GSK-3β signaling pathway

Coronary microembolization (CME) is associated with cardiomyocyte apoptosis and cardiac dysfunction. Puerarin confers protection against multiple cardiovascular diseases, but its effects and specific mechanisms on CME are not fully known. Hence, our study investigated whether puerarin pretreatment could alleviate cardiomyocyte apoptosis and improve cardiac function following CME. The molecular mechanism associated was also explored. A total of 48 Sprague-Dawley rats were randomly divided into CME, CME + Puerarin (CME + Pue), sham, and sham + Puerarin (sham + Pue) groups (with 12 rats per group). A CME model was established in CME and CME + Pue groups by injecting 42 μm microspheres into the left ventricle of rats. Rats in the CME + Pue and sham + Pue groups were intraperitoneally injected with puerarin at 120 mg/kg daily for 7 days before operation. Cardiac function, myocardial histopathology, and cardiomyocyte apoptosis index were determined via cardiac ultrasound, hematoxylin-eosin (H&E) and hematoxylin-basic fuchsin-picric acid (HBFP) stainings, and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. Western blotting was used to measure protein expression related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway. We found that, puerarin significantly ameliorated cardiac dysfunction after CME, attenuated myocardial infarct size, and reduced myocardial apoptotic index. Besides, puerarin inhibited cardiomyocyte apoptosis, as revealed by decreased Bax and cleaved caspase-3, and up-regulated Bcl-2 and PI3K/Akt/GSK-3β pathway related proteins. Collectively, puerarin can inhibit cardiomyocyte apoptosis and thus attenuate myocardial injury caused by CME. Mechanistically, these effects may be achieved through activation of the PI3K/Akt/GSK-3β pathway.     

Preclinical results with I(f) current inhibition by ivabradine

Ivabradine, a highly selective I(f) current inhibitor acting directly on the sinoatrial node, induces a rapid, sustained and dose-dependent reduction of heart rate at rest and during exercise, without significant effects on atrioventricular conduction, left ventricular (LV) contraction-relaxation or vascular tissues. These properties, associated with an improvement in LV loading related to bradycardia, resulted in an increase in stroke volume and preservation of cardiac output at rest and during exercise. Reducing myocardial oxygen consumption and improving oxygen supply, ivabradine reduced the severity of ischaemia and associated regional contractile dysfunction of the stunned myocardium. Long-term administration of ivabradine in rats with chronic heart failure improved cardiac haemodynamics associated with a progressive remodelling of LV structure. In dyslipidaemic mice, ivabradine prevented the renal and cerebrovascular endothelial dysfunction associated with atherosclerosis. These preclinical data suggest that long-term reduction in heart rate with ivabradine might interact with multiple a priori unexpected mechanisms involved in cardiac and vascular remodelling processes associated with chronic heart diseases.     

线粒体功能障碍在心血管疾病中作用机制的研究进展

摘要：线粒体是细胞的能量代谢中心,其通过氧化磷酸化产生能量以满足心脏的高能量需求。心脏许多重要的 生理活动,如心肌收缩和细胞内稳态的维持均需要线粒体产生的三磷酸腺苷（ATP）。因此,完整的线粒体结构和功 能是心脏进行正常生理活动的前提和基础。以呼吸链功能异常和ATP合成障碍为特征的线粒体功能障碍是许多心 血管疾病的发病原因。因此,在疾病早期进行线粒体质量控制、减少线粒体功能障碍和氧化应激成为心血管疾病治 疗的新靶标。本文对线粒体功能障碍在心血管疾病中的作用机制以及相关的新型治疗策略展开综述。     

Interleukin-17 upregulation participates in the pathogenesis of heart failure in mice via NF-κB-dependent suppression of SERCA2a and Cav1.2 expression

Interleukin-17 (IL-17),also called IL-17A,is an important regulator of cardiac diseases,but its role in calcium-related cardiac dysfunction remains to be explor...     

Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria?

The cellular role of mitochondria includes ATP generation and the modulation of cytosolic calcium signals, besides being the "crossroads" for several cell death pathways. The maintenance of optimal mitochondrial functioning during the disease process increases the chances for survival. For example, ischaemia followed by reperfusion is known to negatively affect mitochondrial function, namely by inducing a deleterious condition called mitochondrial permeability transition (MPT). The MPT is responsible for mitochondrial dysfunction and can ultimately lead to cell death. Therefore, it seems important to protect mitochondrial function in cardiac disease. Carvedilol, a beta-adrenergic receptor antagonist with antioxidant properties, has a positive impact on cardiac mitochondria during in vitro, ex-vivo and in vivo models of cardiac dysfunction. Particularly, carvedilol was shown to inhibit MPT in isolated heart mitochondria and protect mitochondria against the oxidative damage induced by the xanthine oxidase/hypoxanthine pro-oxidant system. The observation that carvedilol acts as an inhibitor of mitochondrial complex-I is also of importance, since this mitochondrial system was proposed as cause of the cardiotoxicity associated with the anti-neoplasic drug doxorubicin. This review points out the major findings concerning the positive impact of carvedilol on mitochondrial function and its use in the treatment of myocardial diseases where oxidative stress is known to be involved.     

Exercise training attenuates acute doxorubicin-induced cardiac dysfunction

The use of doxorubicin, a highly effective antitumor antibiotic, is limited by a dose-dependent cardiotoxicity. The purpose of this study was to determine whether chronic exercise training (ET) prior to doxorubicin treatment would preserve cardiac function and reduce myocardial oxidative stress following treatment. Rats were exercise trained on a motorized treadmill or confined to sedentary cage activity for 12 weeks, then administered an intraperitoneal injection of doxorubicin (15 mg/kg) or 0.9% saline. Five days following the injections, hearts were isolated and Langendorf perfused to assess cardiac function and then processed for biochemical analyses. Doxorubicin treatment induced significant inotropic, lusitropic, and chronotropic cardiac dysfunction, reduced coronary flow, and increased cardiac lipid peroxidation in the sedentary animals. Doxorubicin treatment was also associated with a decrease in cardiac manganese superoxide dismutase protein expression and an increase in heat shock protein-72 (Hsp72) compared with saline-treated animals. Exercise training attenuated doxorubicin-induced cardiac dysfunction, and lipid peroxidation, and led to a greater cardiac expression of Hsp72 compared with the sedentary animals. The results of this study demonstrate for the first time that chronic exercise training before doxorubicin treatment protects against cardiac dysfunction following treatment, and provide evidence for a sustained increase in myocardial Hsp72 following exercise training and doxorubicin treatment in vivo.     

Enhancement of calcium uptake via the sarcoplasmic reticulum is a potent therapeutic strategy for dilated cardiomyopathy and heart failure

Dilated cardiomyopathy (DCM), a distinct form of cardiomyopathy, is a myocardial disorder characterised by heart chamber dilation with severe contractile dysfunction and frequent association with heart failure. Analysing this subset of heart failure has provided mechanistic insights of intrinsic pathways for myocyte adaptation and survival. Despite the heterogeneous aetiologies, a calcium cycling defect is common in DCM. A growing body of evidence has shown that calcium homeostasis and calcium-dependent signalling pathways play a pivotal role in cardiac hypertrophy and heart failure. In this regard, recent studies demonstrate that a cardiac calcium cycling defect is identified as a critical regulator for the progression of heart failure in DCM and that enhancement of calcium uptake into the cardiac sarcoplasmic reticulum (SR) may have potential therapeutic value for cardiac dysfunction. This article will focus on the cardiac SR calcium ATPase (SERCA2a) and its regulatory protein, phospholamban (PLB), as new therapeutic targets for DCM and heart failure.     

Sarcoplasmic reticulum and cardiac oxidative stress: an emerging target for heart disease

The sarcoplasmic reticulum (SR) is a major player in maintaining cardiac function, as it is intimately involved in the regulation of Ca2+-movements on a beat-to-beat basis. SR dysfunction due to abnormalities in SR protein content has been reported in different cardiac diseases such as ischaemic heart disease, myocardial infarction, congestive heart failure and various cardiomyopathies; thus the genes expressing the SR Ca2+-pump, Ca2+-channels, calsequestrin, phospholamban and other regulatory proteins are considered important targets for drug development. In our experience, ischaemic preconditioning (IP) and pharmacological therapies, such as anti-oxidants, beta-adrenergic receptor blockers, angiotensin receptor (AT-1) blockers, angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers are effective therapies that improve cardiac performance in the failing heart by improving SR function. Accordingly, this paper is intended to shed light on the knowledge in the field of cardiac therapy targeted to improve and protect SR function.     

Cardiac sodium channels and inherited electrophysiologic disorders: a pharmacogenetic overview

Sodium (Na) channels are essential for cardiac electrical activity. Cardiac Na channel dysfunction, inherited or acquired, can induce life-threatening conduction and arrhythmia disorders. Inherited Na channel dysfunction may put affected patients at a greater risk for these complications when channel-modifying drugs are prescribed. This study addressed pharmacogenetic effects in three well-described Na channel-related diseases: long QT syndrome type 3, Brugada syndrome and inherited cardiac conduction disease. A review of the currently available literature on cardiac Na channel-modulating drugs was undertaken. An overview is given of the known risks of development of the previously mentioned complications of commonly prescribed drugs in patients affected with Na channel-related diseases and the underlying mechanisms.     

Long noncoding RNAs: emerging players in cardiac electrical and structural remodeling

OBJECTIVE Cardiac remodeling results in poor prognosis because of its association with ventricular dysfunction and malignant arrhythmias. METHODS We firstly performed the microarray profiling and bioinformatics analyses of long non-coding RNAs(lnc RNAs) in a mouse model of heart failure(HF) characterized by cardiac remodeling. Then we measured the levels of selected lnc RNAs with high profiles linking to cardiac dysfunction in clinical samples. RESULTS We found that circulating level of ZFAS1 was markedly lower in AMI than in non-AMI subjects. While CCRR is decreased in patients with HF.Then we identified ZFAS1 as an inhibitor of SERCA2 a by binding to SERCA2 a protein. Abnormally increased ZFAS1 in MI impaired cardiac function. Most prominently,we identified a conserved functional domain of ZFAS1,which is much shorter and responsible for its deleterious effects. Moreover, we found CCRR silencing induced arrhythmias by destruction of intercalated discs and gap junctions to slow longitudinal cardiac conduction in healthy mice. CCRR overexpression improves cardiac conduction by blocking endocytic trafficking of connexin43(Cx43) to prevent its degradation via binding to Cx43-interacting protein CIP85. We identified the functional domain of CCRR, which can reproduce the functional roles of full-length CCRR. CONCLUSION Our studies suggest ZFAS1 and CCRR play pivotal roles in cardiac remodeling, and provide therapeutic strategy for ameliorating cardiac dysfunction.     

Inhibition of Dectin-1 in mice ameliorates cardiac remodeling by suppressing NF-κB/NLRP3 signaling after myocardial infarction

The myocardial inflammatory response is a consequence of myocardial infarction (MI), which may deteriorate cardiac remodeling and lead to dysfunction in the heart post-MI. Dectin-1 is a c-type lectin, which has been shown to regulate innate immune responses to pathogens. However, the role of Dectin-1 in the heart diseases remains largely unknown. In this study, we aimed to investigate the effects of Dectin-1 on cardiac remodeling post-MI. We found that cardiac Dectin-1 mRNA and protein expressions were significantly elevated in C57BL/6 mice after MI. In vitro, hypoxia induced cardiomyocyte injury in parallel with increased Dectin-1 protein expression. Knockdown of Dectin-1 remarkably attenuated cardiomyocyte death under hypoxia and lipopolysaccharide (LPS) stimulation. In vivo administration of adeno-associated virus serotype 9 mediated silencing of Dectin-1, which significantly decreased cardiac fibrosis, dilatation, and improved cardiac function in the mice post-MI. At the molecular level, downregulation of Dectin-1 dramatically suppressed up-regulation of nuclear factor-κB (NF-κB), nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), and the inflammatory genes involved in fibrogenesis and cardiac remodeling after MI. Furthermore, treatment with BAY11-7082, an inhibitor of NF-κB, repressed the activation of NF-κB, and attenuated LPS induced elevation of NLRP3 and cell death in cardiomyocytes. Collectively, upregulation of Dectin-1 in cardiomyocytes post-MI contributes to cardiac remodeling and cardiac dysfunction at least partially by activating NF-κB and NLRP3. This study identified Dectin-1 as a promising therapeutic target for ischemic heart disease.     

Genes and their polymorphisms in mono- and multifactorial cardiomyopathies: towards pharmacogenomics in heart failure

Cardiomyopathies are diseases of the myocardium associated with cardiac dysfunction, and are classified as dilated cardiomyopathy (DCM), hypertropic cardiomyopathy (HCM) and restrictive cardiomyopathy. Heart failure and sudden death are the two major complications. Also, since DCM is the primary indication for heart transplantation and HCM the primary cause of sudden death in young athletes, the socioeconomic impact of these diseases is important. Recently, the role of the genetic background in both monogenic and multifactorial cardiomyopathies has been studied, which has led to a better understanding of the underlying mechanisms that promote the development and progression of these diseases. Preliminary data suggest interactions between pharmacological treatment and genetic polymorphisms, which appear to be the first steps towards the application of pharmacogenetics in heart failure.     

Calpain-mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin-induced cardiomyopathy

The critical importance of dystrophin to cardiomyocyte contraction and sarcolemmal and myofibers integrity, led us to test the hypothesis that dystrophin reduction/loss could be involved in the pathogenesis of doxorubicin-induced cardiomyopathy, in order to determine a possible specific structural culprit behind heart failure. Rats received total cumulative doses of doxorubicin during 2 weeks: 3.75, 7.5, and 15 mg/kg. Controls rats received saline. Fourteen days after the last injection, hearts were collected for light and electron microscopy, immunofluorescence and western blot. The cardiac function was evaluated 7 and 14 days after drug or saline. Additionally, dantrolene (5 mg/kg), a calcium-blocking agent that binds to cardiac ryanodine receptors, was administered to controls and doxorubicin-treated rats (15 mg/kg). This study offers novel and mechanistic data to clarify molecular events that occur in the myocardium in doxorubicin-induced chronic cardiomyopathy. Doxorubicin led to a marked reduction/loss in dystrophin membrane localization in cardiomyocytes and left ventricular dysfunction, which might constitute, in association with sarcomeric actin/myosin proteins disruption, the structural basis of doxorubicin-induced cardiac depression. Moreover, increased sarcolemmal permeability suggests functional impairment of the dystrophin-glycoprotein complex in cardiac myofibers and/or oxidative damage. Increased expression of calpain, a calcium-dependent protease, was markedly increased in cardiomyocytes of doxorubicin-treated rats. Dantrolene improved survival rate and preserved myocardial dystrophin, calpain levels and cardiac function, which supports the opinion that calpain mediates dystrophin loss and myofibrils degradation in doxorubicin-treated rats. Studies are needed to further elucidate this mechanism, mainly regarding specific calpain inhibitors, which may provide new interventional pathways to prevent doxorubicin-induced cardiomyopathy.     

Endoplasmic reticulum stress inhibition enhances liver tolerance to ischemia/reperfusion

In many physiopathological conditions, the cell controls its proper dysfunction via activation of the unfolded protein response to restore efficient protein synthesis and folding in the endoplasmic reticulum. However, whether the aim of unfolded protein response is to promote the cell survival, it can also lead to induction of cell death and then affect the cell fate. Recently, endoplasmic reticulum stress appeared to be critical for acute as well as chronic diseases including neurodegeneration, cardiac disease, cancer, obesity, type 2 diabetes, and ischemia/reperfusion injury. Therefore, inhibition of the endoplasmic reticulum stress could constitute a promising therapeutic strategy to limit cellular damage in pathologies such as hepatic ischemia/reperfusion.