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.
"Characterized by an increase in the size of cardiac myocytes and whole heart enlargement, cardiac hypertrophy is an adaptive reaction in response to increased pressure overload. Sustained after-overload usually induces an initial compensatory hypertrophy, which can progress to pathologic cardiac hypertrophy and finally to congestive heart failure . Overpressure is a major initiative stimulus triggering protein synthesis, gene expression reprogramming, and activation of various signaling molecules, such as protein kinase C (PKC) pathway, the mitogen-activated protein kinases (MAPK) pathway, and the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, and, thus, subsequently modifies transcriptional regulatory factors (GATA4) and resulting in cardiac hypertrophy   . "
[Show abstract][Hide abstract] ABSTRACT: Background. Cardiac hypertrophy occurs in many cardiovascular diseases. Apocynum tablet (AT), a traditional Chinese medicine, has been widely used in China to treat patients with hypertension. However, the underlying molecular mechanisms of AT on the hypertension-induced cardiac hypertrophy remain elusive. The current study evaluated the effect and mechanisms of AT on cardiac hypertrophy. Methods. We created a mouse model of cardiac hypertrophy by inducing pressure overload with surgery of transverse aortic constriction (TAC) and then explored the effect of AT on the development of cardiac hypertrophy using 46 mice in 4 study groups (combinations of AT and TAC). In addition, we evaluated the signaling pathway of phosphorylation of ERK1/2, AKT, and protein expression of GATA4 in the cardioprotective effects of AT using Western blot. Results. AT inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, Ser473 site of AKT, and protein expression of GATA4 and significantly inhibited cardiac hypertrophy and cardiac fibrosis at 2 weeks after TAC surgery (P < 0.05). Conclusions. We experimentally demonstrated that AT inhibits cardiac hypertrophy via suppressing phosphorylation of ERK1/2 and AKT.
Evidence-based Complementary and Alternative Medicine 06/2014; 2014(1):769515. DOI:10.1155/2014/769515 · 1.88 Impact Factor
"Following a flurry of investment in previous decades, many pharmacological interventions were met with failure at the stage of progressing into clinical trials, at which point significant investment had already been made and lost. Preclinical testing did not translate into the clinic as expected, and this remains an ongoing problem (Hausenloy & Yellon, 2013; van Berlo et al., 2013). Translational breakthroughs do exist, most notably cyclosporine A infusion for reducing reperfusion injury and SERCA2a gene therapy for restoring pump function in the failing heart. "
[Show abstract][Hide abstract] ABSTRACT: Heart failure is one of the paramount global causes of morbidity and mortality. Despite this pandemic need, the available clinical counter-measures have not altered substantially in recent decades, most notably in the context of pharmacological interventions. Cell death plays a causal role in heart failure, and its inhibition poses a promising approach that has not been thoroughly explored. In previous approaches to target discovery, clinical failures have reflected a deficiency in mechanistic understanding, and in some instances, failure to systematically translate laboratory findings toward the clinic. Here, we review diverse mouse models of heart failure, with an emphasis on those that identify potential targets for pharmacological inhibition of cell death, and on how their translation into effective therapies might be improved in the future.
Current Topics in Developmental Biology 06/2014; 109:171-247. DOI:10.1016/B978-0-12-397920-9.00002-0 · 4.68 Impact Factor
"Various stimuli, including mechanical stress and neurohumoral factors, such as angiotensin II (Ang II), endothelin-1, catecholamine and growth factors, are involved in the progression of cardiac hypertrophy (3). These stimuli activate membrane receptors and intracellular signaling pathways to mediate the transcription of hypertrophy-related genes (4). Enlargement and apoptotic loss of cardiomyocytes are the key pathological changes in cardiac hypertrophy (5). "
[Show abstract][Hide abstract] ABSTRACT: Icariin, the major active component isolated from plants of the Epimedium family, has been reported to have potential protective effects on the cardiovascular system. However, it is not known whether icariin has a direct effect on angiotensin II (Ang II)-induced cardiomyocyte enlargement and apoptosis. In the present study, embryonic rat heart-derived H9c2 cells were stimulated by Ang II, with or without icariin administration. Icariin treatment was found to attenuate the Ang II-induced increase in mRNA expression levels of hypertrophic markers, including atrial natriuretic peptide and B-type natriuretic peptide, in a concentration-dependent manner. The cell surface area of Ang II-treated H9c2 cells also decreased with icariin administration. Furthermore, icariin repressed Ang II-induced cell apoptosis and protein expression levels of Bax and cleaved-caspase 3, while the expression of Bcl-2 was increased by icariin. In addition, 2',7'-dichlorofluorescein diacetate incubation revealed that icariin inhibited the production of intracellular reactive oxygen species (ROS), which were stimulated by Ang II. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 in Ang II-treated H9c2 cells was blocked by icariin. Therefore, the results of the present study indicated that icariin protected H9c2 cardiomyocytes from Ang II-induced hypertrophy and apoptosis by inhibiting the ROS-dependent JNK and p38 pathways.
Experimental and therapeutic medicine 05/2014; 7(5):1116-1122. DOI:10.3892/etm.2014.1598 · 1.27 Impact Factor
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