Article

Signaling effectors underlying pathologic growth and remodeling of the heart

The Journal of clinical investigation (Impact Factor: 13.22). 01/2013; 123(1):37-45. DOI: 10.1172/JCI62839
Source: PubMed
ABSTRACT
Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials.

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    • "While initially pathological hypertrophy can preserve the pumping function and reduce ventricular wall stress, chronically hypertrophy can lead to the development of arrhythmias, heart failure and sudden death [141] . The involvement of IGF-1 in cardiac hypertrophy has long been recognized [94,142] . A relation between IGF-1 levels and ventricular mass was established in patients with abnormal left ventricular diastolic function caused by hypopituitarism [143] . "
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    • "In response to a pathological insult, factors including angiotensin II (Ang II), endothelin 1 (ET-1) and noradrenaline (NE) are released and bind to G q protein-coupled receptors (GPCR) which in turn activate multiple downstream effectors to stimulate hypertrophy. These downstream signalling effectors of Gq include calcineurin, calcium/calmodulindependent protein kinase (CaMK), mitogen activated protein kinases (MAPKs), phospholipase C (PLC), protein kinases (PKC) and histone deacetylases (HDACs)678 . Phosphoinositide 3 kinase (PI3K)[p110g] is also activated by GPCR pathways and negatively regulates cardiomyocyte contractility by modulating the activity of phosphodiesterases (PDEs) and cAMP [11]. "
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    • "While initially pathological hypertrophy can preserve the pumping function and reduce ventricular wall stress, chronically hypertrophy can lead to the development of arrhythmias, heart failure and sudden death [141] . The involvement of IGF-1 in cardiac hypertrophy has long been recognized [94,142] . A relation between IGF-1 levels and ventricular mass was established in patients with abnormal left ventricular diastolic function caused by hypopituitarism [143] . "
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