Journal of molecular and cellular cardiology
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J. Mol. Cell. Cardiol. · Nov 2010
Allogeneic administration of fetal membrane-derived mesenchymal stem cells attenuates acute myocarditis in rats.
We reported previously that the autologous administration of bone marrow-derived mesenchymal stem cells (BM-MSC) significantly attenuated myocardial dysfunction and injury in a rat model of acute myocarditis by stimulating angiogenesis and reducing inflammation. Because BM aspiration procedures are invasive and can yield low numbers of MSC after processing, we focused on fetal membranes (FMs) as an alternative source of MSC to provide a large number of cells. We investigated whether the allogeneic administration of FM-derived MSC (FM-MSC) attenuates myocardial injury and dysfunction in a rat myocarditis model. ⋯ T-lymphocyte activation was significantly reduced by coculture with FM-MSC. The allogeneic administration of FM-MSC attenuated myocardial dysfunction and inflammation, and the host cell-mediated immune response was attenuated in a rat model of acute myocarditis. These results suggest that allogeneic administration of FM-MSC might provide a new therapeutic strategy for the treatment of acute myocarditis.
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J. Mol. Cell. Cardiol. · Aug 2010
Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury.
Vagal nerve stimulation (VS) has been reported to improve the survival after both acute and chronic myocardial infarction through the release of neurotransmitter ACh. However, the precise mechanism behind its beneficial effect is still unknown. In this study, we demonstrate the upregulation of tumor necrosis factor-alpha (TNF-alpha) and its cell survival TNF receptor-2 (TNFR2) as the mechanism behind VS induced myocardial protection. ⋯ Further, ACh upregulated the cell survival TNFR2 expression, while downregulating the cell destructive TNF receptor 1 (TNFR1) expression. These results were confirmed using the TNF receptors deficient mice, where the VS mediated protection was lost both in vivo and in vitro in TNFR2 (TNFR2(-/-)) and TNF receptors double knock out (TNFR1(-/-)2(-/-)) mice. VS and ACh protects the heart against acute ischemia or hypoxic injury by differentially regulating the TNF receptor subtypes.
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J. Mol. Cell. Cardiol. · Jun 2010
Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway.
Bone morphogenetic protein (BMP) signaling regulates embryonic development of many organ systems and defective BMP signaling has been implicated in adult disorders of many of these systems. However, its relevance in cardiac disease has not been reported. Here we demonstrate for the first time that Bmp4 activity promotes cellular apoptosis following ischemia-reperfusion (I/R) injury induced myocardial infarction (MI). ⋯ In contrast, while JNK activation was significantly attenuated in Bmp4(+/)(-) mice and following Smad1 inhibition in myocytes, inhibition of JNK with a specific inhibitory peptide, TAT-JBD(20,) blocked BMP4 induced apoptosis. In vivo treatment of mice with Noggin, an endogenous extracellular BMP antagonist, or dorsomorphin, a small molecule inhibitor of BMP signaling, reduced infarct size, and inhibited pro-apoptotic signaling accompanied by an inhibition of Smad1 phosphorylation and JNK activation. These studies identify a novel role for Bmp4 in the pathogenesis of myocardial infarction and illustrate the use of a small molecule inhibitor of BMP signaling for treatment of acute I/R injury.
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J. Mol. Cell. Cardiol. · May 2010
ReviewMalignant and benign mutations in familial cardiomyopathies: insights into mutations linked to complex cardiovascular phenotypes.
Cardiomyopathies, familial or sporadic, have become recognized as one of the leading cardiac threats. Hypertrophic cardiomyopathy (HCM) affects 0.2% of the population and is the leading cause of sudden death in young adults. Dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) are associated with sudden death as well as heart transplantations. ⋯ Secondly, genetic modifiers are present in some cardiomyopathy patients and are associated with a poorer prognosis. At the protein level, changes in protein-protein interactions may also be important in determining the type of cardiomyopathy caused by different mutations. This review provides insight into the complex cardiovascular phenotypes and genetic variability associated with HCM, DCM, RCM and VNCM.
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J. Mol. Cell. Cardiol. · Dec 2009
Nitric oxide inhibits endothelin-1-induced neonatal cardiomyocyte hypertrophy via a RhoA-ROCK-dependent pathway.
Although nitric oxide (NO) has received extensive attention as an anti-hypertrophic agent the mechanisms underlying its regulation of endothelin-1 (ET-1) have not been fully elucidated. Since RhoA has been identified as an important mediator of cardiac hypertrophy and is inhibited by NO in vascular tissue, we sought to determine whether the anti-ET-1 effects of NO in cardiomyocytes were mediated via inhibition of the RhoA-ROCK cascade in the context of cardiac hypertrophy. Neonatal rat ventricular myocytes were cultured in the presence of ET-1 (10 nM) with or without pre-treatment with the NO donor S-nitroso-n-acetylpenicillamine (SNAP; 100 microM), 8-Br-cGMP (cGMP; 100 microM), the RhoA inhibitor C3 exoenzyme (C3; 30 ng/ml), or the ROCK inhibitor Y-27632 (10 microM). ⋯ In addition, confocal microscopy and Western blotting revealed that 24 h ET-1 treatment reduced the G- to F-actin ratio 67% (p<0.05) which was prevented by SNAP, cGMP, C3 and Y (p<0.05). Taken together, these results suggest that the anti-hypertrophic effects of NO are due, in part, to cGMP-dependent inhibition of the RhoA-ROCK-cofilin signalling pathway. These findings may be important in understanding the mechanisms of anti-ET-1 and anti-hypertrophic effects of NO as well as in the development of novel RhoA-targeted therapeutic interventions for treating cardiac hypertrophy.