Journal of molecular and cellular cardiology
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J. Mol. Cell. Cardiol. · Dec 2011
Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury.
Modulation of purinergic signaling is critical to myocardial homeostasis. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) which converts the proinflammatory molecules ATP or ADP to AMP is a key regulator of purinergic modulation. However, the salutary effects of transgenic over expression of ENTPD-1 on myocardial response to ischemic injury have not been tested to date. ⋯ Resistance to myocardial injury was abrogated by treatment with a non-selective adenosine receptor antagonist, 8-SPT or the more selective A(2B) adenosine receptor antagonist, MRS 1754, but not the A(1) selective antagonists, DPCPX. Additionally, treatment with the ERK 1/2 inhibitor PD98059 or the mitochondrial permeability transition pore opener, atractyloside, abrogated the cardiac protection provided by ENTPDase-1 expression. These results suggest that transgenic ENTPDase-1 expression preferentially conveys myocardial protection from ischemic injury via adenosine A(2B) receptor engagement and associated phosphorylation of the cellular protective signaling molecules, Akt, ERK 1/2 and GSK-3β that prevents detrimental opening of the mitochondrial permeability transition pore.
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J. Mol. Cell. Cardiol. · Nov 2011
Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome.
Circulating microRNAs may have diagnostic potential in acute coronary syndrome (ACS). Previous studies, however, were based on low patient numbers and could not assess the relation of microRNAs to clinical characteristics and their potential prognostic value. We thus assessed the diagnostic and prognostic value of cardiomyocyte-enriched microRNAs in the context of clinical variables and a sensitive myonecrosis biomarker in a larger ACS cohort. ⋯ MiR-133a and miR-208b levels were significantly associated with the risk of death in univariate and age- and gender-adjusted analyses. Both microRNAs lost their independent association with outcome upon further adjustment for hsTnT. The present study tempers speculations about the potential usefulness of cardiomyocyte-enriched microRNAs as diagnostic or prognostic markers in ACS.
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J. Mol. Cell. Cardiol. · Jul 2011
Cyclosporine attenuates cardiomyocyte hypertrophy induced by RAF1 mutants in Noonan and LEOPARD syndromes.
RAS activation is implicated in physiologic and pathologic cardiac hypertrophy. Cross-talk between the Ras and calcineurin pathways, the latter also having been implicated in cardiac hypertrophy, has been suspected for pathologic hypertrophy. Our recent discovery that germ-line mutations in RAF1, which encodes a downstream RAS effector, cause Noonan and LEOPARD syndromes with a high prevalence of hypertrophic cardiomyopathy provided an opportunity to elaborate the role of RAF1 in cardiomyocyte biology. ⋯ Furthermore, treatment with the calcineurin inhibitor cyclosporine blocked hypertrophy in NRCMs and ARCMs overexpressing RAF1. Thus, we have identified calcineurin as a novel interaction partner for RAF1 and established a mechanistic link and possible therapeutic target for pathological cardiomyocyte hypertrophy induced by mutant RAF1. This article is part of a Special Issue entitled 'Possible Editorial'.
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J. Mol. Cell. Cardiol. · Jan 2011
Survivin: a novel player in insulin cardioprotection against myocardial ischemia/reperfusion injury.
Insulin inhibits ischemia/reperfusion-induced myocardial apoptosis through the activation of a survival signaling cascade including the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. However, the down-stream mechanism of PI3K remains elusive. This study is aimed at investigating whether survivin (SVV) plays a role in the insulin-induced anti-apoptotic effect in the ischemic/reperfused (I/R) hearts, and if so, further determining the signaling mechanism involved. ⋯ To further ascertain the role of SVV in insulin-induced cardioprotection, cardiomyocytes were transfected with adenovirus encoding SVV (gain-of-function) or siRNA targeting SVV (loss-of-function). Overexpression of SVV decreased I/R-induced cardiomyocyte apoptosis in vitro, while siRNA targeting SVV significantly blunted the anti-apoptotic effect of insulin. Taken together, these results suggest a novel role of PI3K/Akt/mTOR/SVV signaling in the cardioprotective effect of insulin.