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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]

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]

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]