The mammalian heart is a dynamic organ that can grow and change to accommodate alterations in its workload. During development and in response to physiological stimuli or pathological insults, the heart undergoes hypertrophic enlargement, which is characterized by an increase in the size of individual cardiac myocytes. Recent findings in genetically modified animal models implicate important intermediate signal-transduction pathways in the coordination of heart growth following physiological and pathological stimulation.

Background-Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. Methods and Results-Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. Conclusions-Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesisand is suitable for therapeutic intervention in the setting of ischemic heart disease. (Circulation. 2011;124:720-730.)Key Words: myocardial infarction Ⅲ microRNAs Ⅲ angiogenesis Ⅲ antagomir Ⅲ gene expression Ⅲ heart failure M yocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. MI leads to scar formation and left ventricular remodeling, including cardiac dilatation, contractile dysfunction, cardiomyocyte hypertrophy, and fibrosis. 1 Tissue hypoxia triggers endothelial apoptosis, and insufficient capillary density further contributes to an increase of infarct size and left ventricular dysfunction. [2][3][4] Clinical Perspective on p 730MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules that regulate a substantial fraction of the genome by binding to the 3Ј untranslated region (3ЈUTR) of frequently coordinately acting target messenger RNAs. 5 MiRNAs have been identified as valuable therapeutic targets in a variety of diseases, including cardiovascular disease. 6 -12 Inhibition of miRNA processing by genetic knockdown of Dicer expression impairs endothelial functions and angiogenesis. [13][14][15] Certain miRNAs are important regulators of endothelial function, especially angiogenesis. 7,13-17 A subset of miRNAs is regulated by tissue oxygen levels, and miR-24 is activated by hypoxic conditions via the hypoxia-inducible factor 1 (HIF-1). 18 Although miR-24 is expressed in a variety Received April 19, 2011; accepted June 7, 2011 Table I). The small RNA...

Background-Cardiac cachexia is characterized by an exaggerated loss of skeletal muscle, weakness, and exercise intolerance, although the cause of these effects remains unknown. Here, we hypothesized that the heart functions as an endocrine organ in promoting systemic cachexia by secreting peptide factors such as myostatin. Myostatin is a cytokine of the transforming growth factor-␤ superfamily that is known to control muscle wasting. Methods and Results-We used a Cre/loxP system to ablate myostatin (Mstn gene) expression in a cell type-specific manner. As expected, elimination of Mstn selectively in skeletal muscle with a myosin light chain 1f (MLC1f)-cre allele induced robust hypertrophy in all skeletal muscle. However, heart-specific deletion of Mstn with an Nkx2.5-cre allele did not alter baseline heart size or secondarily affect skeletal muscle size, but the characteristic wasting and atrophy of skeletal muscle that typify heart failure were not observed in these heart-specific null mice, indicating that myocardial myostatin expression controls muscle atrophy in heart failure. Indeed, myostatin levels in the plasma were significantly increased in wild-type mice subjected to pressure overload-induced cardiac hypertrophy but not in Mstn heart-specific deleted mice. Moreover, cardiac-specific overexpression of myostatin, which increased circulating levels of myostatin by 3-to 4-fold, caused a reduction in weight of the quadriceps, gastrocnemius, soleus, and even the heart itself. Finally, to investigate myostatin as a potential therapeutic target for the treatment of muscle wasting in heart failure, we infused a myostatin blocking antibody (JA-16), which promoted greater maintenance of muscle mass in heart failure. Conclusions-Myostatin released from cardiomyocytes induces skeletal muscle wasting in heart failure. Targeted inhibition of myostatin in cardiac cachexia might be a therapeutic option in the future. (Circulation. 2010;121:419-425.)