Systems analysis reveals down-regulation of a network of prosurvival miRNAs drives the apoptotic response in dilated cardiomyopathy

miRNA expression in early stage mouse model of dilated cardiomyopathy Apoptosis is a hallmark of multiple etiologies of heart failure, including dilated cardiomyopathy. Since microRNAs are master regulators of cardiac development and key effectors of intracellular signaling, they represent novel candidates for understanding the mechanisms driving the increased dysfunction and loss of cardiomyocytes during cardiovascular disease progression. To determine the role of cardiac miRNAs in the apoptotic response, we used microarray technology to monitor miRNA levels in a validated murine phospholambam mutant model of dilated cardiomyopathy. 24 miRNAs were found significantly differentially expressed, most of which have not been linked to cardiac disease before. We showed that individual silencing of 6 out of 7 significantly down-regulated miRNAs (mir-1, -29c, -30d, -149, -486, -499)  led to a strong apoptotic phenotype in cell culture , suggesting they repress pro-apoptotic factors. To identify putative miRNA targets most likely relevant to cell death, we computationally integrated transcriptomic, proteomic and functional annotation data. We showed the dependency of prioritized target abundance on miRNA expression using RNA interference and quantitative mass spectrometry. We concluded that down regulation of key pro-survival miRNAs causes up-regulation of apoptotic signaling effectors that contribute to cardiac cell loss, potentially leading to system decompensation and heart failure. Two different microarray platforms, were used to identify and quantify miRNA expression at early stage dilated cardiomyopathy times. Total RNA was collected from mouse ventricle tissues in a transgenic model expressing a mutant form of phospholamban which results in dilated cardiomyopathway versus healthly littermates as a control.