Signaling effectors underlying pathologic growth and remodeling of the heart.
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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ABSTRACT: Leonurus heterophyllus sweet has been suggested to have cardioprotective effects against heart diseases, including ischemic diseases and ventricular remodeling. However, the active ingredients of the herb and the underlying mechanisms are poorly understood. The aim of the present study was to investigate the effects of stachydrine (STA), a major constituent of Leonurus heterophyllus sweet, on norepinephrine (NE) induced hypertrophy and the changes of calcium transients in neonatal rat cardiomyocytes. Ventricular myocytes from 1-day-old Wistar rats were isolated and cultured in DMEM/F12 with 1 mumol/L norepinephrine in the presence or absence of 10 mumol/L STA for 72 h. Cardiomyocytes hypertrophy was evaluated by cell surface area, total protein/DNA content, beta/alpha-MHC mRNA ratio. While calcium handling function was evaluated by Ca2+-transient amplitude and decay, SERCA2a activity and expression, PLN expression and phosphorylation. beta1-adrenergic receptor system activation was evaluated by the content of cAMP and the activation of PKA. NE treatment increases the cell surface area, protein synthesis, the expression level of beta-MHC and beta/alpha-MHC ratio. These effects were attenuated by STA. NE-induced hypertrophy was associated with increased Ca2+-transient amplitude, accelerated decay of the Ca2+-transient, increased phospholamban expression, hyper-phosphorylation at both the serine-16 and threonine-17 residues, increased intracellular cAMP level, and PKA overactivation. All of which were significantly inhibited by STA. These data suggest that STA attenuates norepinephrine-induced cardiomyocyte hypertrophy and has potential protective effects against beta-adrenergic receptor induced Ca2+ mishandling.BMC Complementary and Alternative Medicine 12/2014; 14(1):474. DOI:10.1186/1472-6882-14-474 · 1.88 Impact Factor
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ABSTRACT: Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropriate or incomplete preclinical studies. In these guidelines, we present a number of recommendations to enhance similarity between HF animal models and the human condition in order to reduce the chances of failure in subsequent clinical trials. We propose different approaches to address safety as well as efficacy of new therapeutic products. We also propose that good practice rules are followed from the outset so that the chances of eventual approval by regulatory agencies increase. We hope that these guidelines will help improve the translation of results from animal models to humans and thereby contribute to more successful clinical trials and development of new therapies for HF.Journal of Cardiovascular Translational Research 01/2015; DOI:10.1007/s12265-015-9606-8 · 3.06 Impact Factor
- 06/2014; 1(1):83-97. DOI:10.3390/jcdd1010083