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      Diacylglycerol Kinase ζRescues Gαq-Induced Heart Failure in Transgenic Mice

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          TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy.

          Angiotensin (Ang) II participates in the pathogenesis of heart failure through induction of cardiac hypertrophy. Ang II-induced hypertrophic growth of cardiomyocytes is mediated by nuclear factor of activated T cells (NFAT), a Ca(2+)-responsive transcriptional factor. It is believed that phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP(3)) is responsible for Ca(2+) increase that is necessary for NFAT activation. However, we demonstrate that PLC-mediated production of diacylglycerol (DAG) but not IP(3) is essential for Ang II-induced NFAT activation in rat cardiac myocytes. NFAT activation and hypertrophic responses by Ang II stimulation required the enhanced frequency of Ca(2+) oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca(2+) channel. Patch clamp recordings from single myocytes revealed that Ang II activated DAG-sensitive TRPC-like currents. Among DAG-activating TRPC channels (TRPC3, TRPC6, and TRPC7), the activities of TRPC3 and TRPC6 channels correlated with Ang II-induced NFAT activation and hypertrophic responses. These data suggest that DAG-induced Ca(2+) signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy.
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            Induction of cardiac fibrosis by transforming growth factor-beta(1).

            The role of transforming growth factor-beta(1) (TGF-beta(1)) in the production and deposition of collagens and in the induction of gene expression in the myocardium in relation to the development of myocardial fibrosis will be discussed. Very low expression of TGF-beta(1) and collagen type I and III mRNA is seen in the normal rat heart. Both expressions are markedly increased in the infarcted heart and the levels of TGF-beta(1) mRNA precedes increases in mRNA levels for extracellular matrix (ECM) proteins, suggesting a possible role of TGF-beta(1) in remodeling processes in the myocardium. The TGF-beta(1) expression is normally only transient since continuous TGF-beta(1) overexpression seems to promote nonadaptive cardiac hypertrophy and myocardial fibrosis. In vitro, TGF-beta(1) induces an increase in collagen production and secretion and enhances the abundance of mRNA levels for collagen type I and III in rat cardiac fibroblasts in culture. TGF-beta(1) also stimulates in vivo the expression of ECM proteins and in vivo gene transfer of TGF-beta(1) can induce myocardial fibrosis. Increased myocardial TGF-beta(1) and ECM protein mRNA are found in myocardial fibrosis induced by angiotensin II infusion, by noradrenaline treatment, by isoprenaline infusion, and by long-term blockade of NO synthesis. In vivo antagonism of TGF-beta(1) by neutralizing anti-TGF-beta(1) antibodies or by proteoglycans prevents the increase in gene expression of ECM proteins and inhibits myocardial fibrosis, suggesting that the increases in matrix protein production and fibrosis are mediated by TGF-beta(1). Copyright 2000 Academic Press.
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              Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction.

              Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and transduce similar signals as interleukin-1 receptor in response to exogenous pathogens. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, that may contribute to ventricular remodeling after myocardial infarction. In this study, we determined whether TLR-2 was involved in cardiac remodeling after myocardial infarction. Myocardial infarction was induced by surgical left anterior descending coronary artery ligation on wild-type (WT) mice and TLR-2-knockout (KO) mice. The survival rate was significantly higher in KO mice than in WT mice 4 weeks after myocardial infarction (65% versus 43%, P<0.03). Infarct size and degree of inflammatory cell infiltration in infarct area were similar between WT and KO mice. However, myocardial fibrosis in the noninfarct area of KO mice was much less than in WT mice (P<0.01) and was accompanied by reduced transforming growth factor-beta1 and collagen type 1 mRNA expressions (P<0.01 and P<0.05, respectively). Left ventricular dimensions at end diastole were smaller in KO mice than in WT mice at 1 week (P<0.05) and 4 weeks (P<0.01) after surgery. Furthermore, fractional shortening was higher (27.7+/-2.5% versus 21.2+/-2.6%, P<0.05, at 1 week, and 24.3+/-2.0% versus 16.6+/-2.5%, P<0.01, at 4 weeks) in KO mice compared with WT mice. These data suggest that TLR-2 plays an important role in ventricular remodeling after myocardial infarction.
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                Author and article information

                Journal
                Circulation Journal
                Circ J
                Japanese Circulation Society
                1346-9843
                1347-4820
                2008
                2008
                : 72
                : 2
                : 309-317
                Article
                10.1253/circj.72.309
                © 2008

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