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Common cardiovascular diseases, such as atherosclerosis and congestive heart failure, are exceptionally complex, involving a multitude of environmental and genetic factors that often show nonlinear interactions as well as being highly dependent on sex, age, and even the maternal environment. Although focused, reductionistic approaches have led to progress in elucidating the pathophysiology of cardiovascular diseases, such approaches are poorly powered to address complex interactions. Over the past decade, technological advances have made it possible to interrogate biological systems on a global level, raising hopes that, in combination with computational approaches, it may be possible to more fully address the complexities of cardiovascular diseases. In this Review, we provide an overview of such systems-based approaches to cardiovascular disease and discuss their translational implications. [ABSTRACT FROM AUTHOR]

During pregnancy, healthy women develop ventricular hypertrophy and diastolic dysfunction as a result of volume overload as well as increased stretch and force demand. Pregnancy also induces electrocardiogram disturbances such as longer QT-interval dispersion. Surprisingly, it was not until recently that the underlying molecular mechanisms or the role of sex hormones was addressed in this critical female reproductive stage. Recent work with the use of mouse and rat models show that the molecular signature of pregnancy-related hypertrophy differs from that of a pathologic form in that classic gene markers (e.g., myosin heavy chains [α and β], atrial natriuretic peptide, phospholamban, and sarcoplasmic reticulum Ca2+-ATPase) remain unchanged. However, both types of hypertrophies have the commonality of a reduced expression of the Kv4.3 channel, a membrane protein that can prevent cardiac hypertrophy when overexpressed. Increased estrogen in late pregnancy may be a mechanism to induce Kv4.3 protein downregulation and increased activity of the stretch-activated c-Src kinase. Cellular/molecular mechanisms used to make a pregnant woman''s heart work more efficiently and recover to normal cardiac function postpartum are beginning to emerge as cardioprotective natriuretic peptides– and NO–cGMP cascades get upregulated postpartum. This exciting initial work calls for more research in this underexplored area that should set the basis for better treatment of women during pregnancy. [Copyright &y& Elsevier]

Discusses advances in techniques for studying cardiac disease using the mouse as a model system. Cardiac overload as one of the most important stimuli for development of hypertrophy and heart failure in humans; Examination of murine cardiac physiology in vivo with microtransducers; Conventional histology and markers.

Abstract: The p38 mitogen-activated protein kinases (p38s) are stress-activated Ser/Thr kinases. Their activation has been associated with various pathological stressors in the heart. Activated p38 is implicated in a wide spectrum of cardiac pathologies, including hypertrophy, myocardial infarction, as well as systolic and diastolic heart failure. In this review, the specific contribution of different isoforms of p38 kinases to cardiac diseases as well as TAB-1-mediated non-canonical activation pathway are discussed as a rationale for inhibiting p38 activity to treat cardiac hypertrophy, ischemic injury, and heart failure. Finally, a summary of current clinical trials targeting p38 kinases in cardiovascular diseases is provided to highlight the potential promise as well as existing challenges of this therapeutic approach. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure.” [Copyright &y& Elsevier]

Cardiac pressure load stimulates hypertrophy, often leading to chamber dilation and dysfunction. ROS contribute to this process. Here we show that uncoupling of nitric oxide synthase-3 (NOS3) plays a major role in pressure load-induced myocardial ROS and consequent chamber remodeling/hypertrophy. Chronic transverse aortic constriction (TAC; for 3 and 9 weeks) in control mice induced marked cardiac hypertrophy, dilation, and dysfunction. Mice lacking NOS3 displayed modest and concentric hypertrophy to TAC with preserved function. NOS3(-/-) TAC hearts developed less fibrosis, myocyte hypertrophy, and fetal gene re-expression (B-natriuretic peptide and alpha-skeletal actin). ROS, nitrotyrosine, and gelatinase (MMP-2 and MMP-9) zymogen activity markedly increased in control TAC, but not in NOS3(-/-) TAC, hearts. TAC induced NOS3 uncoupling in the heart, reflected by reduced NOS3 dimer and tetrahydrobiopterin (BH4), increased NOS3-dependent generation of ROS, and lowered Ca(2+)-dependent NOS activity. Cotreatment with BH4 prevented NOS3 uncoupling and inhibited ROS, resulting in concentric nondilated hypertrophy. Mice given the antioxidant tetrahydroneopterin as a control did not display changes in TAC response. Thus, pressure overload triggers NOS3 uncoupling as a prominent source of myocardial ROS that contribute to dilatory remodeling and cardiac dysfunction. Reversal of this process by BH4 suggests a potential treatment to ameliorate the pathophysiology of chronic pressure-induced hypertrophy. [ABSTRACT FROM AUTHOR]

Presents information on a study that examined the role of the Grb2 adapter protein and p38 MAPK in cardiac hypertrophy. Methodologies of the study; Results of the study; Discussion on the study.

Introduction: Branched-chain amino acid (BCAA) catabolic defect is recently recognized as a disease driver in heart failure; however, the molecular mechanisms underlying its impairment and pathogenic effect remain underexplored. Elevated ROS production and disrupted redox homeostasis are prevailing features in the diseased heart, but the BCAA catabolic pathway as a target for ROS via oxidative stress-sensitive PTMs (O-PTMs) has never been systematically investigated in the context of pathological stress in heart. Methods: We studied 7 highly prevalent O-PTM types in the cardiac proteome of a cardiac hypertrophy mouse model in response to chronic ISO treatment. We characterized the O-PTM response and measured plasma BCAA metabolite levels in a temporal fashion across 6 genetic strains. Permutation test on O-PTM features identified key O-PTM alterations associated with ISO-induced hypertrophy. Cubic spline-based clustering discerned O-PTM temporal dynamics. Results: We identified 28 proteins involved in the BCAA catabolic pathway with 357 modifications by 7 O-PTM types, 326 conserved between mouse and human. Four or more distinct temporal patterns portraying O-PTM landscape under ISO were identified. Permutation test extracted molecular signatures consisting of 7 key O-PTM sites, many of which exhibited significant reduction in occupancy in ISO treatment. Furthermore, our metabolomics study identified marked accumulation of plasma BCAAs that reached their peak levels post-ISO (3-5 days), corroborating our previous findings on impaired BCAA flux and transcriptional loss of BCAA pathway genes in both human HF and pressure-overload mouse hearts. Taken together, ISO provoked dynamic alterations of O-PTMs on BCAA enzymes, which may have also contributed to impairment of BCAA catabolic activities at the PTM level. Conclusions: BCAA catabolic pathway proteins underwent diverse O-PTM alterations following ISO-induced oxidative stress challenge. Our computational platform enables the extraction of key O-PTM sites, their temporal patterns, and their underlying relationships with cardiac hypertrophy. [ABSTRACT FROM AUTHOR]