Recent studies indicate that the downstream mediators of cardiac Ang II/TGF-β networking may include Smad proteins, TGFβ1 -activated kinase-1 (TAK1), and induction of hypertrophic responsiveness to h-adrenergic stimulation in cardiac myocytes [46]. One study investigating the intracellular signaling events that are required for AngIIdependent upregulation of TGF-β1 revealed that the induction of TGF-β1 mRNA by Ang II in adult ventricular cardiomyocytes is mediated by NAD(P)H oxidase, and subsequent activation of protein kinase C (PKC), p38- MAP kinase, and nuclear Activating-Protein-1 (AP-1) binding activity [43] (Fig. 5), Moreover,in cultured cardiac fibroblasts, Ang II directly promotes TGF-β11/Smad signaling by elevating Smad 2 levels and inducing the translocation of phosphorylated Smad 2 into the nuclei, and these responses also depend on the AT1 receptor [80], indicating that cross-talk between Ang II and TGF-β1at the postreceptor level (Smad signaling) may be associated with fibrosis in cardiac remodeling.

Progressive contractile dysfunction of viable myocardium that surrounds a large infarct leads to heart failure following acute myocardial infarction (AMI) [91]. Experimental evidence indicates Stem cell-based therapy is being considered as an alternative treatment for cardiomyopathy[38]. And may improve the left ventricular (LV) contractile performance.In one study ,by comparig the effect of transplantation of (MAPCs), (BMCs) or fibroblasts on post-infarct cardiac function,they found transplantation of MAPCs significantly improved LV contractile function for at least 8 weeks post-transplantation; Significantly more inflammatory cells were present in MAPC- than BMC-treated hearts at 1 week, which was accompanied by increased vascularity 8 weeks post-transplantation.Later, they concluded MAPCs indirectly contributed to these effects, by secreting MCP-1,VEGF,PDGF-BB,and TGFbeta1, and others, resulting in increased angiogenensis and cardioprotection[91, 90].

Self-assembling heart-derived stem cell clusters named cardiospheres (CSps) ,by investigating the two divergent cell processing methods to enhance cellular potency and humoral activity,the observers demonstrated that combined transplantation of specifically-processed human secondary cardiosphere (CSs) enhances infarct repair through the complementary enhancement of cardiopoietic regenerative and paracrine protective effect,which is consistent with that CSps improve function and attenuate remodeling in rodent models of acute modelmyocardial infarction [86, 38].Later, one study showed cardiosphere transplantation enhances angiogenesis and reduces fibrosis in chronically infarcted myocardium, leading to partial reversal of cardiac dysfunction. The underlying mechanism involves inhibition of Tgf-β1/smad signaling by CSp-secreted soluble endoglin[38, 65].

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