Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CCN1 (Cyr61) is a secreted matricellular protein, mediating angiogenesis and cell survival through interaction with integrins. Although CCN1 expression is induced in the heart during ischemia and pressure overload, its function in cardiac myocytes remains to be elucidated. We hypothesized that CCN1 may not only induce angiogenesis but may also have a direct effect on cardiac myocytes during ischemia. In this study, we investigated the effect of CCN1 on survival of cardiac myocytes under oxidative stress and examined a signal transduction pathway downstream of CCN1. A solid-phase binding assay demonstrated that CCN1 was bound to cardiac myocytes in a dose-dependent, saturable manner. Inactivation of beta1 integrin in cardiac myocytes inhibited binding with CCN1, indicating that CCN1 was bound to cardiac myocytes via beta1 integrin. Knockdown of endogenous CCN1 decreased the number of surviving cells under oxidative stress, while pretreatment of cardiac myocytes with recombinant CCN1 significantly increased the number of surviving cells. Moreover, TUNEL staining showed that CCN1 significantly decreased apoptotic cells. Furthermore, treatment of cardiac myocytes with CCN1 induced phosphorylation of Akt and extracellular signal-regulated kinase (ERK). Inactivation of beta1 integrin inhibited CCN1-induced phosphorylation of these kinases and abolished the protective effect of CCN1. Moreover, pretreatment of cells with wortmannin completely blocked the protective effect of CCN1 on cardiac myocytes under oxidative stress, indicating that the protective effect of CCN1 was mainly mediated by activation of Akt. The antiapoptotic effect of CCN1 on cardiac myocytes together with its proangiogenic property could be beneficial in the treatment of ischemic heart disease.
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PMID:CCN1 protects cardiac myocytes from oxidative stress via beta1 integrin-Akt pathway. 1731 59

Genetic manipulation of key components of the evolutionally conserved Hippo pathway has shown that the precise control of these signaling molecules is critical to cardiac development and response to stresses. However, how this pathway is involved in the progression of cardiac dysfunction in different heart diseases remains unclear. We investigated the expressional levels and subcellular localization of Yap1, Taz, and Tead1 and determined Hippo target gene expression in failing human hearts with ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (IDC) and mouse desmin-related cardiomyopathy (DES). Our results demonstrated that Yap1, Taz, and Tead1 were significantly increased in failing human and DES hearts compared with the non-failing controls (NFH) or wild type (WT) mouse hearts at both mRNA and protein levels. Interestingly, adult human and mouse hearts had more Taz than Yap1 by mRNA and protein expression and their increases in diseased hearts were proportional and did not change Yap1/Taz ratio. Yap1, Taz, and Tead1 were accumulated in the nuclear fraction and cardiomyocyte nuclei of diseased hearts. The ratio of Yap1 phosphorylated at serine 127 (human) or serine 112 (mouse) to the total Yap1 (pYap1/Yap1) was significantly lower in the nuclear fraction of diseased hearts than that in normal controls. More importantly, Hippo downstream targets Ankrd1, Ctgf, and Cyr61 were transcriptionally elevated in the diseased hearts. These results suggest that Yap1/Taz signaling is activated in human and mouse dysfunctional hearts. Further investigation with relevant animal models will determine whether this pathway is a potential target for preventing and reversing abnormal remodeling during the progression of different cardiac disorders.
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PMID:Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy. 2915 88