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Aims The Toll-like receptor 7 (TLR7) is an intracellular innate immune receptor activated by nucleic acids shed from dying cells leading to activation of the innate immune system. Since innate immune system activation is involved in the response to myocardial infarction (MI), this study aims to identify if TLR7 is involved in post-MI ischaemic injury and adverse remodelling after MI. Methods and results TLR7 involvement in MI was investigated in human tissue from patients with ischaemic heart failure, as well as in a mouse model of permanent left anterior descending artery occlusion in C57BL/6J wild type and TLR7 deficient (TLR7−/−) mice. TLR7 expression was up-regulated in human and mouse ischaemic myocardium after MI. Compared to wild type mice, TLR7−/− mice had less acute cardiac rupture associated with blunted activation of matrix metalloproteinase 2, increased expression of tissue inhibitor of metalloproteinase 1, recruitment of more myofibroblasts, and the formation of a myocardial scar with higher collagen fibre density. Furthermore, inflammatory cell influx and inflammatory cytokine expression post-MI were reduced in the TLR7−/− heart. During a 28-day follow-up after MI, TLR7 deficiency resulted in less chronic adverse left ventricular remodelling and better cardiac function. Bone marrow (BM) transplantation experiments showed that TLR7 deficiency in BM-derived cells preserved cardiac function after MI. Conclusions In acute MI, TLR7 mediates the response to acute cardiac injury and chronic remodelling probably via modulation of post-MI scar formation and BM-derived inflammatory infiltration of the myocardium. [ABSTRACT FROM AUTHOR]

Aims Obesity and type 2 diabetes (T2D) trigger a harmful stress-induced cardiac remodeling process known as cardiomyopathy. These diseases represent a serious and widespread health problem in the Western world; however the underlying molecular basis is not clear. ATF3 is an 'immediate early' gene whose expression is highly and transiently induced in response to multiple stressors such as metabolic, oxidative, endoplasmic reticulum and inflammation, stressors that are involved in T2D cardiomyopathy. The role of ATF3 in diabetic cardiomyopathy is currently unknown. Our research has aimed to study the effect of ATF3 expression on cardiomyocytes, heart function and glucose homeostasis in an obesity-induced T2D mouse model. Methods and results We used wild type mice (WT) as well as mutant mice with a cardiac-specific ATF3 deficiency (ATF3-cKO). Mice were fed a high-fat diet (HFD) for 15 weeks. HFD induced high ATF3 expression in cardiomyocytes. Mice were examined for cardiac remodeling processes and the diabetic state was assessed. HFD-fed ATF3-cKO mice exhibited severe cardiac fibrosis, higher levels of heart hypertrophic markers, increased inflammation and worse cardiac function, as compared to WT mice. Interestingly, HFD-fed ATF3-cKO mice display increased hyperglycemia and reduced glucose tolerance, despite higher blood insulin levels, as compared to HFD-fed WT mice. Elevated levels of the cardiac inflammatory cytokines IL-6 and TNFα leading to impaired insulin signalling may partially explain the peripheral glucose intolerance. Conclusions Cardiac ATF3 has a protective role in dampening the HFD-induced cardiac remodeling processes. ATF3 exerts both local and systemic effects related to T2D-induced cardiomyopathy. This study provides a strong relationship between heart remodeling processes and blood glucose homeostasis. [ABSTRACT FROM AUTHOR]

Aims: Although increased Na+/Ca2+ exchanger 1 (NCX1) expression is observed during heart failure (HF), the pathological role of NCX1 during the progression of HF remains unclear. We examined alterations of NCX1 expression and activity in hearts after transverse aortic constriction (TAC) surgery and explored whether NCX1 influences pressure overloadinduced pathological cardiac remodelling. Methods and results: We generated novel transgenic mice in which NCX1 expression is controlled by a cardiac-specific, doxycycline (DOX)- dependent promoter. In the absence of DOX, TAC surgery caused substantial chamber dilation with a gradual decrease in contractility by 16 weeks. Cardiomyocytes showed a decline in contractility with abnormal Ca2+ handling during excitation- contraction (E-C) coupling. Reduced NCX1 activity was observed 8 weeks after TAC and was still apparent at 17 weeks. Induced NCX1 overexpression by DOX treatment starting 8 weeks after TAC returned NCX1 activity to pre-TAC levels and prevented chamber dilation with cardiac dysfunction. DOX treatment not only upregulated NCX1 expression in TAC-operated hearts but also returned L-type Ca2+ channel and sarcoplasmic reticulum (SR) Ca2+ ATPase expression levels to those in sham-operated hearts. In DOX-treated myocytes, contractility, T-tubule integrity, synchrony of Ca2+ release from the SR, and Ca2+ handling during E-C coupling was preserved 16 weeks after TAC surgery. In addition, DOX treatment attenuated the down-regulation of survival signalling and up-regulation of apoptosis signalling 16 weeks after TAC surgery. Conclusion: Induced overexpression of NCX1 attenuated pressure overload-induced pathological cardiac remodelling. Thus, maintaining NCX1 activity may be a potential therapeutic strategy for preventing the progression of HF. [ABSTRACT FROM AUTHOR]

Aims: Postinfarction remodelling is accompanied and influenced by perturbations in MAPK signalling. The Growth arrest and DNA-damage-inducible 45 (Gadd45) proteins are small acidic proteins involved in DNA repair and modulation of MAPK activity. Little is known about the role of Gadd45 in the heart. Here, we explored the potential contribution of Gadd45 gamma (γ) isoform to the acute and late phase of heart failure (HF) after myocardial infarction (MI) and determine the mechanisms underlying Gadd45γ actions. Methods and results: The Gadd45γ isoform is upregulated in murine cardiomyocytes subject to simulated ischemia and in the mouse heart during MI. In order to mimic the situation observed during MI, we enhanced Gadd45γ content in cardiomyocytes with a single injection of an adeno-associated viral (AAV9) vector encoding Gadd45γ under the cTNT promoter. Gadd45γ overexpression induces cardiomyocyte apoptosis, fibrosis, left ventricular dysfunction and HF. On the other hand, genetic deletion of Gadd45γ in KO mice confers resistance to ischemic injury, at least in part by limiting cardiomyocyte apoptosis. Mechanistically, Gadd45γ activates RIP1 and caspase-8 in a p38 MAPK-dependent manner to promote cardiomyocyte death. Conclusions: This work is the first to demonstrate that Gadd45? accumulation during MI promotes the development and persistence of HF by inducing cardiomyocyte apoptosis in a p38 MAPK-dependent manner. We clearly identify Gadd45γ as a therapeutic target in the development of HF. [ABSTRACT FROM AUTHOR]

Aims Cardiac remodelling is one of the key pathological changes that occur with cardiovascular disease. Previous studies have demonstrated the beneficial effects of CYP2J2 expression on cardiac injury. In the present study, we investigated the effects of cardiomyocyte-specific CYP2J2 expression and EET treatment on angiotensin II-induced cardiac remodelling and sought to determine the underlying molecular mechanisms involved in this process. Methods and results Eight-week-old mice with cardiomyocyte-specific CYP2J2 expression (αMHC-CYP2J2-Tr) and wild-type (WT) control mice were treated with Ang-II. Ang-II treatment of WT mice induced changes in heart morphology, cardiac hypertrophy and dysfunction, as well as collagen accumulation; however, cardiomyocyte-specific expression of CYP2J2 attenuated these effects. The cardioprotective effects observed in α-MHC-CYP2J2-Tr mice were associated with peroxisome proliferator-activated receptor (PPAR)-γ activation, reduced oxidative stress, reduced NF-κB p65 nuclear translocation, and inhibition of TGF-β1/smad pathway. The effects seen with cardiomyocyte-specific expression of CYP2J2 were partially blocked by treatment with PPAR-γ antagonist GW9662. In in vitro studies, 11,12-EET(1 μmol/L) treatment attenuated cardiomyocyte hypertrophy and remodelling-related protein (collagen I, TGF-β1, TIMP1) expression by inhibiting the oxidative stress-mediated NF-κB pathway via PPAR-γ activation. Furthermore, conditioned media from neonatal cardiomyocytes treated with 11,12-EET inhibited activation of cardiac fibroblasts and TGF-β1/smad pathway. Conclusion Cardiomyocyte-specific expression of CYP2J2 or treatment with EETs protects against cardiac remodelling by attenuating oxidative stress-mediated NF-κBp65 nuclear translocation via PPAR-γ activation. [ABSTRACT FROM PUBLISHER]

Aims Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach. Methods and results Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusin's overexpression strongly reduced mortality (43.2% in wild-type vs. 27.3% in melusin-TG, P = 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. Conclusions Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling. [ABSTRACT FROM AUTHOR]

Aims Toll-interacting protein (Tollip) is a critical regulator of the Toll-like receptor-mediated signalling pathway. However, the role of Tollip in chronic pressure overload-induced cardiac hypertrophy remains unclear. This study aimed to determine the functional significance of Tollip in the regulation of aortic banding-induced cardiac remodelling and its underlying mechanisms. Methods and results First, we observed that Tollip was down-regulated in human failing hearts and murine hypertrophic hearts, as determined by western blotting and RT–PCR. Using cultured neonatal rat cardiomyocytes, we found that adenovirus vector-mediated overexpression of Tollip limited angiotensin II-induced cell hypertrophy; whereas knockdown of Tollip by shRNA exhibited the opposite effects. We then generated a transgenic (TG) mouse model with cardiac specific-overexpression of Tollip and subjected them to aortic banding (AB) for 8 weeks. When compared with AB-treated wild-type mouse hearts, Tollip-TGs showed a significant attenuation of cardiac hypertrophy, fibrosis, and dysfunction, as measured by echocardiography, immune-staining, and molecular/biochemical analysis. Conversely, a global Tollip-knockout mouse model revealed an aggravated cardiac hypertrophy and accelerated maladaptation to chronic pressure overloading. Mechanistically, we discovered that Tollip interacted with AKT and suppressed its downstream signalling pathway. Pre-activation of AKT in cardiomyocytes largely offset the Tollip-elicited anti-hypertrophic effects. Conclusion Our results provide the first evidence that Tollip serves as a negative regulator of pathological cardiac hypertrophy by blocking the AKT signalling pathway. [ABSTRACT FROM AUTHOR]

Aims Activation of the β1-adrenergic receptor and its G protein, Gs, induces cardiac hypertrophy. However, activation of classic Gαs effectors, adenylyl cyclases (AC) and protein kinase A, is not sufficient for induction of hypertrophy, which suggests the involvement of additional pathway(s) activated by Gs. Recently, we discovered that βγ subunits of Gq induce phosphorylation of the extracellular regulated kinases 1 and 2 (Erk1/2) at threonine188 and thereby induce hypertrophy. Here we investigated whether β-adrenergic receptors might also induce cardiac hypertrophy via ErkThr188 phosphorylation. Methods and results β-Adrenergic receptor activation induced ErkThr188 phosphorylation in mouse hearts and in neonatal cardiomyocytes. Inhibition of Erk1/2 or overexpression of ErkThr188 phosphorylation-deficient mutants (Erk2T188A and Erk2T188S) significantly attenuated β–adrenergic cardiomyocyte hypertrophy in vitro. Erk activity was stimulated by both isoproterenol and the direct AC activator forskolin, but only isoproterenol induced ErkThr188 phosphorylation. ErkThr188 phosphorylation required Gβγ released from Gs and was prevented by Gβγ inhibition. Similarly, isoproterenol, but not forskolin, induced nuclear accumulation of Erk and cardiomyocyte hypertrophy. Long-term application of isoproterenol in mice caused left ventricular hypertrophy and cardiac remodelling, and this was reduced in Erk2T188S transgenic mice, supporting the physiological relevance of ErkThr188 phosphorylation. Conclusions Activation of Gs by β-adrenergic receptors leads to (i) canonical Erk1/2 activation via AC, and (ii) release of Gβγ, which then associates with activated Erk1/2 and induces ErkThr188 phosphorylation, causing nuclear accumulation of Erk and ultimately cardiomyocyte hypertrophy. These findings reveal a new pathway critically involved in β-adrenergically mediated cardiac hypertrophy and may yield new therapeutic strategies against hypertrophic remodelling. [ABSTRACT FROM AUTHOR]

Aims Plasma levels of cardiotrophin-1 (CT-1) are elevated in several cardiovascular diseases and are correlated with the severity of the pathology. However, the mechanisms by which this inflammatory cytokine participates in the pathology of the heart are not completely understood. It is well established that alterations in intracellular calcium ([Ca2+]i) handling are involved in cardiac dysfunction during heart failure, but it is unknown whether CT-1 modulates [Ca2+]i handling in adult cardiomyocytes. Here we have analyzed for the first time the effects of CT-1 on [Ca2+]i homeostasis in adult rat cardiomyocytes. Methods and results L-type calcium current (ICaL) was recorded using patch-clamp techniques, and [Ca2+]i transients and Ca2+ sparks were viewed by confocal microscopy. Treatment of cardiomyocytes with 1 nM CT-1 for 20–60 min induced a significant increase in ICaL density, [Ca2+]i transients, and cell shortening compared with control cells. Our study reveals that CT-1 increases ICaL by a protein kinase A-dependent mechanism, and Ca2+ sparks by a Ca2+/calmodulin kinase II-dependent and protein kinase A-independent mechanism. Cardiomyocytes treated with CT-1 exhibited a higher occurrence of arrhythmogenic behaviour, manifested as spontaneous Ca2+ waves and aftercontractions. Conclusion Our findings provide evidence that cardiomyocytes treated with CT-1 present high spontaneous Ca2+ release during diastole, a mechanism linked to arrhythmogenicity in the pathologic heart. [ABSTRACT FROM AUTHOR]

Aims Myocardial infarction (MI) results in acute impairment of left ventricular (LV) function through the initial development of cardiomyocyte death and subsequent progression of LV remodelling. The expression of syndecan-4 (Sdc4), a transmembrane proteoglycan, is up-regulated after MI, but its function in the heart remains unknown. Here, we characterize the effects of Sdc4 deficiency in murine myocardial ischaemia and permanent infarction. Methods and results Targeted deletion of Sdc4 (Sdc4–/–) leads to increased myocardial damage after ischaemic–reperfusion injury due to enhanced cardiomyocyte apoptosis associated with reduced activation of extracellular signal-regulated kinase in cardiomyocytes in vitro and in vivo. After ischaemic–reperfusion injury and permanent infarction, we observed an increase in cardiomyocyte area, nuclear translocation of nuclear factor of activated T cells (NFAT), and transcription of the NFAT target rcan1.4 in wild-type mice. NFAT pathway activation was enhanced in Sdc4–/– mice. In line with the in vivo data, NFAT activation and hypertrophy occurs in isolated cardiomyocytes with reduced Sdc4 expression during phenylephrine stimulation in vitro. Despite the initially increased myocardial damage, echocardiography revealed improved LV geometry and function in Sdc4–/– mice 7 days after MI. Conclusion Interception of the Sdc4 pathway enhances infarct expansion and hypertrophic remodelling during early infarct healing in ischaemic–reperfusion injury and permanent infarction mouse models and exerts net beneficial effects on LV function. [ABSTRACT FROM PUBLISHER]

Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic volume overload secondary to aortocaval fistula and mitral regurgitation. Accordingly, mast cells have been implicated to have a major role in the pathophysiology of these cardiovascular disorders. In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. Recent results have shown that with chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. However, the role of the cardiac mast cell is not one dimensional, with evidence from hypertension and cardiac transplantation studies suggesting that they can also assume a pro-fibrotic phenotype in the heart. These adverse events do not occur in mast cell deficient rodents or when cardiac mast cells are pharmacologically prevented from degranulating. This review is focused on the regulation and dual roles of cardiac mast cells in: (i) activating MMPs and causing myocardial fibrillar collagen degradation and (ii) causing fibrosis in the stressed, injured or diseased heart. Moreover, there is strong evidence that premenopausal female cardioprotection may at least partly be due to gender differences in cardiac mast cells. This too will be addressed. [ABSTRACT FROM AUTHOR]

Aims The role of nuclear factor (NF)-κB in heart failure (HF) is not well defined. We sought to determine whether myocyte-localized NF-κB p65 activation in HF exacerbates post-infarction remodelling and promotes maladaptive endoplasmic reticulum (ER) stress. Methods and results Non-transgenic (NTg) and transgenic (Tg) mice with myocyte-restricted overexpression of a phosphorylation-resistant inhibitor of κBα (IκBαS32A,S36A) underwent coronary ligation (to induce HF) or sham operation. Over 4 weeks, the remote myocardium of ligated hearts exhibited robust NF-κB activation that was almost exclusively p65 beyond 24 h. Compared with sham at 4 weeks, NTg HF hearts were dilated and dysfunctional, and exhibited hypertrophy, fibrosis, up-regulation of inflammatory cytokines, increased apoptosis, down-regulation of ER protein chaperones, and up-regulation of the ER stress-activated pro-apoptotic factor CHOP. Compared with NTg HF, Tg-IκBαS32A,S36A HF mice exhibited: (i) improved survival, chamber remodelling, systolic function, and pulmonary congestion, (ii) markedly diminished NF-κB p65 activation, cytokine expression, and fibrosis, and (iii) a three-fold reduction in apoptosis. Moreover, Tg-IκBαS32A,S36A HF hearts exhibited maintained expression of ER chaperones and CHOP when compared with sham. In cardiomyocytes, NF-κB activation was required for ER stress-mediated apoptosis, whereas abrogation of myocyte NF-κB shifted the ER stress response to one of adaptation and survival. Conclusion Persistent myocyte NF-κB p65 activation in HF exacerbates cardiac remodelling by imparting pro-inflammatory, pro-fibrotic, and pro-apoptotic effects. p65 modulation of cell death in HF may occur in part from NF-κB-mediated transformation of the ER stress response from one of adaptation to one of apoptosis. [ABSTRACT FROM AUTHOR]

Variation in the human glucocorticoid receptor (GR) gene associates with relative glucocorticoid resistance, hypertension and increased cardiovascular disease risk. Here, the contribution of cardiovascular GR to disease risk was assessed in male and female "SMGRKO" mice with cardiomyocyte and vascular smooth muscle deletion of GR.SMGRKO mice, generated by crossing GR “floxed” mice (congenic on C57BL/6J) with SM22α-Cre mice, have reduced cardiac GR protein and mRNA levels (by 52% and 57%, respectively), compared to Cre-negative littermate controls. Loss of cardiovascular GR impairs viability. There are fewer SMGKRO mice than controls at weaning with a greater effect in females [SMGRKO:Control; females 27:79(25% vs expected 50%); males 37:68(35%) p<0.0001].Doppler measurements (Visualsonics Vevo770 ultrasound) of blood flow within the left ventricle show a detrimental increase in the myocardial performance index, which measures combined systolic and diastolic function, in both sexes of adult SMGRKO mice. This is primarily due to prolonged isovolumetric contraction time (p<0.05) indicating impairment of the initial left ventricular contractile phase.In male SMGRKO mice (but not female) heart weight (% body weight) was increased (Control:0.50±0.02%; SMGRKO:0.55±0.01%, p<0.05) as was cardiomyocyte cross sectional area (Control:180±4μm2; SMGRKO:194±4μm2, p<0.01). Furthermore, cardiac levels of mRNA encoding myosin heavy chain-β, a marker of pathological cardiac hypertrophy, were elevated in male SMGRKO mice only (p<0.05). Both sexes showed left ventricular fibrosis (histopathology) and elevated levels of cardiac mRNA encoding pro-fibrotic factors.Thus, cardiomyocyte/smooth muscle GR-deficiency causes the same functional impairment of isovolumetric contraction but differential pathological changes in the left ventricle of surviving male and female mice. Whether pathology is worse in neonatal or fetal SMGRKO females is under investigation. These findings support a role for cardiovascular GR in determination of cardiovascular disease risk, though without overt signs of cardiac hypertrophy in females. [ABSTRACT FROM PUBLISHER]

Purpose: The ability of granulocyte colony-stimulating factor (GCSF) to mobilize endothelial progenitor cells (EPCs), as well as to protect cardiomyocytes at risk and to regenerate cardiomyocyte has attracted considerable attention. We hypothesized that G-CSF could improve left ventricular function and remodeling in patients with post-myocardial infarction heart failure.Methods: G-CSF (5.0 mg/kg/day) for 5 days, was administered subcutaneously to 24 patients with post-myocardial infarction heart failure (NYHA functional class II-III). Global left ventricular ejection fraction and left ventricular end-systolic and end-diastolic volumes were assessed by echocardiography. The effects of G-CSF on blood were measured by auto hematology analyzer and semi-auto chemistry analyzer. Flow cytometric analysis of circulating CD34+ hematopoietic progenitor cells was performed.Results: G-CSF increased the white blood cells significantly in the circulation (from 7.7 ±0.3 to 25.2±0.9 x103/ml, p<0.001) and CD34+ cells (from 1.37±0.12 to 23.51±5.37 cells/mL, p<0.001). Indices of platelets, hemoglobin, alanine aminotransferase, lactic dehydrogenase, and uric acid were not changed by treatment. At 1 month post-treatment, there was significant improvement of global left ventricular ejection fraction (43.05 ± 2.94 versus 53.91 ± 2.60 %, p<0.01); and improved left ventricular end-systolic (178.0 ± 8.3 versus 117.3 ± 5.3 ml, p<0.01) and end-diastolic volume (247.0 ± 11.0 versus 180.0± 7.5 ml, p<0,01). All patients reported mild myalgia which were easily managed with acetaminophen.Conclusions: The results show that G-CSF mobilizes stem cells from bone marrow and improve left ventricular function and remodeling in patients with heart failure. The treatment strategy was safe and tolerable in patients with post-myocardial infarction heart failure. [ABSTRACT FROM PUBLISHER]

Background: Postinfarction remodeling is accompanied and influenced by perturbations in oxidative stress status and MAPK signaling. The Growth arrest and DNA-damage-inducible 45 (Gadd45) proteins are small acidic proteins involved in modulation of MAPK activities. Despite its relationship with p38 MAPK and intense interest in the cancer field, little is known about the role of Gadd45 in the heart. Our aim is to explore the potential contribution of Gadd45 gamma (γ) isoform to the acute and late phase of heart failure after myocardial infarction (MI).Methods and results: MI was induced in wild-type (WT) versus Gadd45 γ (KO) littermates by left anterior descending coronary artery ligation. Pre-MI, WT, and KO hearts had comparable chamber dimensions and ventricular function, but as early as 1 week post-MI, KO mice had significantly less left ventricular dilatation and dysfunction than WT mice. The left ventricular dilatation and dysfunction, hypertrophy and fibrosis remained better in the KO mice throughout the study (4 weeks). Given the significant reduction in left ventricular function evident as early as 1 week post-MI, we examined the infarct size following a 24-hour coronary artery ligation and found it to be decreased in the KO mice. This decreased susceptibility to ischemic injury–induced apoptosis was also seen in cardiomyocytes isolated from the KO mice that were exposed to hypoxia. In addition, necroptosis activity pathway (RIP1-3; caspase 8) was reduced in the KO mice.To mimic the Gadd45 γ overexpression observed during MI and to better understand its crucial role during cardiomyopathy development, we injected 3 10^11 of cTNT-Gadd45 γ AAV9 particles i.v. and studied the cardiac function, fibrosis and biological markers of cardiac dysfunction. Four weeks after the cTNT-Gadd45 γ AAV9 injection, we observed a decrease in the cardiac function and an increase in the heart dilatation compared to the GFP AAV9 injected control mice. A remodeling process is engaging with more fibrosis after 4 weeks and it is associated with p38 MAPK and necroptosis pathway activation.Conclusion: Gadd45 γ promotes ischemic injury, accentuates post-MI remodeling and left ventricular dysfunction, and increases the progression to heart failure. The lost of gadd45 γ confers resistance to ischemic injury, at least in part, via limiting necroptosis pathway through a p38 MAPK dependant mechanism. This work, demonstrate the importance of Gadd45 γ/p38 MAPK complex in the development and persistence of heart failure, particularly in the balance of the cell death process. [ABSTRACT FROM PUBLISHER]

Aims Sustained hypertension leads to cardiac hypertrophy that can progress, through pathological remodelling, to heart failure. Abnormality of the renin–angiotensin system (RAS) has been strongly implicated in this process. Although hypertrophy in human is an established risk factor independent of blood pressure (BP), separation of remodelling in response to local cues within the differentiated myocardium from that related to pressure overload is unresolved. This study aimed to clarify the role of local RAS activity, specifically in the adult heart, in modulating cardiac hypertrophy and pathological remodelling. Methods and results Transgenic mice with inducible cardiomyocyte-specific expression of a wild-type or N111G mutant form of the human angiotensin II (Ang II) type-1 receptor (hAT1R) were generated. The wild-type receptor is primarily stimulated by Ang II. In contrast, the N111G receptor can also be fully stimulated by the Ang II derivative, Ang IV, at levels that do not stimulate the wild-type receptor. The unique properties of these models were used to investigate the myocardial growth, remodelling and functional responses to hAT1R stimulation, specifically in adult cardiomyocytes, under normal conditions and following Ang IV infusion. Low-level expression of wild-type or N111G hAT1R at the cardiomyocyte membrane, from the onset of adolescence, induced enhanced myocyte growth and associated cardiac hypertrophy in the adult. This was not associated with change in resting BP or heart rate, measured by longitudinal telemetric analysis, and did not progress to pathological remodelling or heart failure. However, selective activation of cardiomyocyte-specific N111G receptors by Ang IV peptide infusion induced adverse ventricular remodelling within 4 weeks. This was characterized by increased interstitial fibrosis, dilatation of the left ventricle, and impaired cardiac function. Conclusion Low-level local AT1R activity in differentiated myocardium causes compensated cardiac hypertrophy, that is, increased myocardial mass but with the retention of normal function, whereas short-term increased stimulation induces cardiac dysfunction with dilatation, reduced ejection fraction, and increased fibrosis in the absence of change in systemic BP. [ABSTRACT FROM AUTHOR]

The intricate mechanisms responsible for the structural remodelling of the myocardium that facilitates the evolution to heart failure in hypertensive patients, namely in those with left ventricular hypertrophy, requires from clinicians the utilization of a multibiomarker approach for short-term and long-term stratification as well as prognostication of patients. Biochemical markers may also help to identify patients with no clinical evidence of hypertensive heart disease, and provide information about the need for more aggressive therapy during different stages of the disease, and potentially provide valuable biochemical data for the specialist. Although there is a continuous and complex interplay between biochemical and imaging markers, perhaps their use will also have the potential to modify the medical management of patients with hypertensive heart disease and therapeutic decision-making by tailoring a targeted therapy according to the predominant mechanism of myocardial remodelling. This article will review in brief the most relevant information on a panel of circulating molecules that may accomplish the criteria required to be considered as biochemical markers of the cardiomyocyte and non-cardiomyocyte structural changes that occur in the hypertensive myocardium. [ABSTRACT FROM AUTHOR]

Cardiac action potentials (APs) are driven by ionic currents flowing through specific channels and exchangers across cardiomyocyte membranes. Once initiated by rapid Na+ entry during phase 0, the AP time course is determined by the balance between inward depolarizing currents, carried mainly by Na+ and Ca2+, and outward repolarizing currents carried mainly by K+. K+ currents play a major role in repolarization. The loss of a K+ current can impair repolarization, but there is a redundancy of K+ currents so that when one K+ current is dysfunctional, other K+ currents increase to compensate, a phenomenon called ‘repolarization reserve’. Repolarization reserve protects repolarization under conditions that increase inward current or reduce outward current, threatening the balance that governs AP duration. This protection comes at the expense of reduced repolarization reserve, potentially resulting in unexpectedly large AP prolongation and arrhythmogenesis, when an additional repolarization-suppressing intervention is superimposed. The critical role of appropriate repolarization is such that cardiac rhythm stability can be impaired with either abnormally slow or excessively rapid repolarization. In cardiac disease states such as heart failure and atrial fibrillation (AF), changes in ion channel properties appear as part of an adaptive response to maintain function in the face of disease-related stress on the cardiovascular system. However, if the stress is maintained the adaptive ion channel changes may themselves lead to dysfunction, in particular cardiac arrhythmias. The present article reviews ionic remodelling of cardiac repolarization, and focuses on how potentially adaptive repolarization changes with congestive heart failure and AF can have arrhythmogenic consequences. [ABSTRACT FROM AUTHOR]

It is commonly held that cardiac remodelling, represented by changes in muscle mass, size, and shape of the heart, explains the progression of congestive heart failure (CHF). However, this concept does not provide any clear information regarding the development of cardiac dysfunction in CHF. Extensive research has revealed that various subcellular organelles such as the extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus undergo varying degrees of changes in their biochemical composition and molecular structure in CHF. This subcellular remodelling occurs due to alterations in cardiac gene expression as well as activation of different proteases and phospholipases in the failing hearts. Several mechanisms including increased ventricular wall stress, prolonged activation of the renin–angiotensin and sympathetic systems, and oxidative stress have been suggested to account for subcellular remodelling in CHF. Furthermore, subcellular remodelling is associated with changes in cardiomyocyte structure, cation homeostasis as well as functional activities of cation channels and transporters, receptor-mediated signal transduction, Ca2+-cycling proteins, contractile and regulatory proteins, and energy production during the development of heart failure. The existing evidence supports the view that subcellular remodelling may result in cardiac dysfunction and thus play a critical role in the transition of cardiac hypertrophy to heart failure. [ABSTRACT FROM AUTHOR]

In human and experimental myocardial infarction (MI), cessation of blood supply leads to rapid necrosis of cardiac myocytes in the ischaemic heart. Immediately after injury, various intra- and intercellular pathways contribute to healing the myocardial wound in order to achieve tissue integrity and function. MI and the consequent loss of myocardium are the major aetiology for heart failure. Despite aggressive primary therapy, prognosis remains poor in patients with large infarction and severe left ventricular dysfunction. Thus, it would be highly desirable to improve healing of the cardiac wound to maintain structure and function of the heart. Healing in the heart occurs in overlapping phases. Herein, we review the inflammatory phase as a trigger of tissue formation. [ABSTRACT FROM AUTHOR]

A defining cellular event in the transition from compensated hypertrophy to dilated cardiomyopathy is cardiomyocyte drop-out due to apoptosis, programmed necrosis, and autophagy. The importance of apoptosis in heart failure has been recognized for over a decade, while other forms of programmed cell death have more recently been appreciated, and their pathophysiological roles continue to be defined in experimental and clinical heart failure. The major focus of this review is on apoptosis in heart failure, with a discussion of molecular cross-talk between apoptosis, autophagy, and programmed necrosis. [ABSTRACT FROM AUTHOR]