Calcineurin signalling mechanisms in myocardial hypertrophy

Calcineurin dephosphorylates multiple serine residues near the N terminus of NFAT proteins enabling them to translocate from cytoplasm to nucleus, where they activate a subset of hypertrophic response genes. Transgenic mice over-expressing a constitutively active form of calcineurin or NFAT3, developed obviously hypertrophy and heart failure or sudden death proving its pathogenic role. Here we used literatures on MEDLINE (2000-2011), systematically reviewed the new development of calcineurin signaling pathway in myocardial hypertrophy (J Geriatr Cardiol 2010; 7:189-192).     

Calcineurin signalling mechanisms in myocardial hypertrophy

Calcineurin dephosphorylates multiple serine residues near the N terminus of NFAT proteins enabling them to translocate from cytoplasm to nucleus, where they activate a subset of hypertrophic response genes. Transgenic mice over-expressing a constitu- tively active form of calcineurin or NFAT3, developed obviously hypertrophy and heart failure or sudden death proving its pathogenic role. Here we used literatures on MEDLINE （2000-2011）, systematically reviewed the new development of calcineurin signaling pathway in myocardial hypertrophy     

Molecular mechanisms of myocardial infarction

Despite an increased knowledge of risk factors for atherosclerotic heart disease, it remains nearly endemic in Western society. Despite the high penetrance, only a fraction of those with the disease progress to develop a frank myocardial infarction (MI). Over the past decade, it has become clear that inflammation plays an important role in the pathogenesis of MI. Inflammatory arterial disease therefore may be a better term for the subset of patients that develop the serious adverse consequences related to the rupture of the intracoronary plaque. Using newer molecular techniques such as high-throughput SNP analysis, genome-wide scanning, and enriched pedigree analysis, many of the specific mechanisms underlying the inflammatory milieu involved in this transition have been elucidated and may help identify those at risk for the adverse events associated with atherosclerotic disease.     

Molecular and cellular mechanisms of mechanical stress-induced cardiac hypertrophy

Congestive heart failure is one of the major issues for cardiologists. Since cardiac hypertrophy deteriorates into heart failure, it is important to elucidate the mechanisms of cardiac hypertrophy. Hemodynamic overload, namely mechanical stress, is a major cause for cardiac hypertrophy. Mechanical stress induces various hypertrophic responses such as activation of phosphorylation cascades of many protein kinases, expression of specific genes and an increase in protein synthesis. During this process, secretion and production of vasoactive peptides such as angiotensin II and endothelin-1, are increased and play critical roles in the induction of these hypertrophic responses. Recently, a Ca2+ dependent protein kinase, CaMK, and a Ca2+ dependent protein phosphatase, calcineurin, have attracted great attention as critical molecules that induce cardiac hypertrophy. In this review, we described the mechanisms by which mechanical stress induces cardiac hypertrophy, especially focusing on the role of calcineurin in the development of cardiac hypertrophy.     

Molecular determinants of myocardial hypertrophy and failure: alternative pathways for beneficial and maladaptive hypertrophy.

The implementation of molecular biological approaches has led to the discovery of single genetic variations that contribute to the development of cardiac failure. In the present review, the characteristics that are invariably associated with the development of failure in experimental animals and clinical studies are discussed, which may provide attractive biological targets in the treatment of human heart failure. Findings from the Framingham studies have provided evidence that the presence of left ventricular hypertrophy is the main risk factor for subsequent development of heart failure in man. Conventional views identify myocardial hypertrophy as a compensatory response to increased workload, prone to evoke disease. Recent findings in genetic models of myocardial hypertrophy and human studies have provided the molecular basis for a novel concept, which favours the existence of either compensatory or maladaptive forms of hypertrophy, of which only the latter leads the way to cardiac failure. Furthermore, the concept that hypertrophy compensates for augmented wall stress is probably outdated. In this article, we provide the molecular pathways that can distinguish beneficial from maladaptive hypertrophy.     

Regulatory mechanisms of myocardial hypertrophy and fibrosis: results of in vivo studies.

Left ventricular hypertrophy is a major risk factor associated with the appearance of adverse cardiovascular events. A distortion in myocardial structure, mediated by an abnormal accumulation of fibrillar collagen within the adventitia of intramyocardial coronary arteries and neighbouring interstitial spaces, alters the electrical and mechanical behaviour of the myocardium. The mechanisms responsible for the regulation of cardiac myocyte growth and collagen accumulation are therefore of considerable interest. Herein we review results of in vivo studies conducted in the authors' laboratory that addressed these issues in various experimental models. The findings indicate that in arterial hypertension myocardial hypertrophy is related to ventricular systolic pressure work. Myocardial fibrosis, on the other hand, is not related to haemodynamic workload, but rather the presence of mineralocorticoid excess relative to sodium intake and excretion. Accordingly, fibrosis can appear in both the hypertensive left and non-hypertensive right ventricles. Pharmacological probes, administered in variable doses, were used to further test and support this hypothesis. In both primary and secondary hyperaldosteronism, it was possible to prevent the pathological structural remodelling of the myocardium with an aldosterone receptor antagonist, while in unilateral renal ischaemia ACE inhibition was similarly cardioprotective. Other studies demonstrated that it was feasible to regress the fibrous tissue response and normalise diastolic stiffness. This concept of cardioreparation suggests that heart failure due to this type of structural remodelling may be reversible.     

Statins and myocardial hypertrophy

Cardiac hypertrophy is a physiological adaptive response by the heart to pressure overload. However, after prolonged periods, this initial adaptive response becomes maladaptive, leading to increased mortality and morbidity from heart failure. Recently, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been shown to inhibit cardiac hypertrophy by cholesterol-independent mechanisms. Statins block the isoprenylation and activation of members of the Rho guanosine triphosphatase (GTPase) family, such as RhoA and Rac1. Since Rac1 is a requisite component of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is a major source of reactive oxygen species (ROS) in cardiovascular cells, the ability of statins to inhibit Rac1-mediated oxidative stress makes an important contribution to their inhibitory effects on cardiac hypertrophy.     

Idiopathic myocardial hypertrophy

The records of twenty-one patients with idiopathic myocardial hypertrophy observed during a period of five years were reviewed. On the basis of their dominant clinical course these cases could be classified into three groups: (1) severe intractable congestive heart failure; (2) minimal to moderate congestive heart failure; (3) symptoms referable primarily to an associated portal cirrhosis. The cause of this disorder remains obscure. However, in the first two groups there is speculation that some of the cases might be congenital in origin.The clinical features were related to the underlying congestive heart failure and to pulmonary and systemic emboli which at times dominated the picture. The electrocardiogram in typical cases showed left ventricular hypertrophy or intraventricular conduction disturbances, normal or left axis deviation and a characteristic biphasic P wave in lead V₁. Roentgenograms of the chest showed globular cardiac enlargement. Cardiac catheterization and ballistocardiographic data were consistent with congestive heart failure.Histologic examination of the heart revealed myocardial hypertrophy usually associated with focal interstitial fibrosis. Over one half of cases undergoing necropsy revealed intramural thrombi in the left ventricle.The possible etiologic factors and the differential diagnosis of this condition were considered. The diagnosis of idiopathic myocardial hypertrophy is suggested by the presence of cardiomegaly in relatively young normotensive adults with gallop sounds, absent organic murmurs and electrocardiographic criteria of both left atrial and left ventricular enlargement irrespective of the presence or absence of congestive phenomena.     

Functional mechanisms of myocardial microcirculation in left ventricular hypertrophy: a hypothetical model of capillary remodeling post myocardial infarction

OBJECTIVES: Left ventricular (LV) remodeling after myocardial infarction (MI) is characterized by myocyte hypertrophy and a disproportional capillary growth. We developed a hypothetical model of capillary remodeling mechanisms based on quantitative data of microcirculation determined by magnetic resonance (MR) imaging techniques and histology. METHODS: Perfusion and regional capillary blood volume (RBV) were quantified 8 and 16 weeks after MI (mean 27.0+/-2.9% of the left ventricle 16 weeks post MI) or sham operation in rats using MR imaging and were correlated with morphometric data. RESULTS: Maximum perfusion (ml/(g min)) in the remote area decreased from 5.69+/-0.63 to 3.48+/-0.48 compared to sham animals (5.33+/-0.31, p相似文献   

Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction

The extent of cardiac remodeling determines survival after acute MI. However, the mechanisms driving cardiac remodeling remain unknown. We examined the effect of ischemia and reperfusion (R) on myocardial changes up to 6 days post-MI. Pigs underwent 1.5 h or 4 h mid-LAD balloon occlusion and sacrificed or 1.5 h occlusion followed by R and sacrificed at 2.5 h, 1 day, 3 days, and 6 days. Ischemic- (IM) and non-ischemic myocardium (NIM) was obtained for molecular analysis of: 1) apoptosis (P-Bcl2, Bax, P-p53, active-caspase-3); 2) the TLR-4-MyD88-dependent and independent pathways; 3) Akt/mTOR/P70^S6K axis activation; and, 4) fibrosis (TGF-β, collagen1-A1/A3). Histopathology for inflammation, collagen, and fibroblast content, TUNEL staining, and metalloproteinase activity was performed. Apoptosis is only detected upon R in IM cardiomyocytes and progresses up to 6 days post-R mainly associated with infiltrated macrophages. The Akt/mTOR/P70^s6K pathway is also activated upon R (IM) and remains elevated up to 6 days-R (P < 0.05). Ischemia activates the TLR-4-MyD88-dependent (cytokines/chemokines) and -independent (IRF-3) pathways in IM and NIM and remains high up to 6 days post-R (P < 0.05). Accordingly, leukocytes and macrophages are progressively recruited to the IM (P < 0.05). Ischemia up-regulates pro-fibrotic TGF-β that gradually rises collagen1-A1/-A3 mRNA with subsequent increase in total collagen fibrils and fibroblasts from 3 days-R onwards (P < 0.005). MMP-2 activity increases from ischemia to 3 days post-R (P < 0.05). We report that there is a timely coordinated cellular and molecular response to myocardial ischemia and R within the first 6 days after MI. In-depth understanding of the mechanisms involved in tissue repair is warranted to timely intervene and better define novel cardioprotective strategies.     

Pathophysiological aspects of myocardial hypertrophy

Heart hypertrophy in response to increased workload is a complex process in which this organ adapts to the environment by increasing the muscle mass in terms of additional contractile units and formation of different types of contractile proteins (myosin isozymes). In addition, augmentation of membrane function with respect to calcium transport activities of sarcolemma and sarcoplasmic reticulum occurs at early stages of cardiac hypertrophy associated with hyperfunction of the myocardium. However, if cardiac hypertrophy is left unattended beyond a certain period, physiological hypertrophy is converted to pathological hypertrophy whereby the cardiac muscle is unable to generate an adequate amount of contractile activity. It appears that the sympathetic nervous system is activated for producing beneficial effects at early stages but an elevated level of sympathetic tone for a prolonged period could result in dysfunction of the cardiac muscle. The transition of physiological hypertrophy to pathological hypertrophy seems to be due to the occurrence of intracellular calcium overload in the myocardial cell as a consequence of defects in the membrane calcium transport systems. It is suggested that careful attention should be paid not only to removal of the stimulus responsible for cardiac hypertrophy but also to lowering sympathetic tone. Efforts should also be made to prevent the occurrence of intracellular calcium overload due to membrane defects.     

心肌细胞肥大的信号转导

心肌肥大的启动和发展涉及到多种细胞外信号及相应的多条细胞内信号转导通路,其信号转导通路的研究是当前研究热点,本文从蛋白激酶途径、丝裂原活化蛋白激酶、小G蛋白途径等,综述了心肌细胞肥大的信号转导研究.