Heart Failure (HF) results from cardiomyocyte (CM) hypertrophy and apoptosis, combined with cardiac fibroblast (CF) proliferation and fibrosis; these are hallmarks of cardiac pathological remodelling, which is accompanied by changes in the expression of specific miRNAs and mitochondrial-encoded genes (MEGs). Early stage cardiac hypertrophy (CH) induces compensatory mitochondrial protein translation. Endpoint HF is accompanied by reduced mitochondrial protein synthesis and dysfunctional mitochondria. It is generally accepted that restoring mitochondrial protein expression and function mitigates HF progression, highlighting the importance of clarifying gene regulation mechanisms in mitochondria to guide development of improved HF therapeutics. Many studies have examined mechanisms that coordinate mRNA transcription of nuclear-encoded mitochondrial genes (NEMGs) and MEGs. However, regulatory mechanisms of MEG mRNA translation and its coordination with NEMG mRNA translation in the heart remain virtually unexplored. We have identified a miR-574-Fam210a axis that maintains the optimal translation of MEGs and mitochondrial homeostasis in both CM and CF, as a compensatory cardioprotective pathway at an early stage of CH. In contrast to most other single strand miRNAs, miR-574 produces 2 functional strands, miR-574-5p and miR-574-3p. At early stage of CH, miR-574-5p antagonizes Fam210a expression in CM to prevent excessive MEG expression, enhanced ROS production and impaired mitochondrial activity, thereby preventing CM hypertrophy and apoptosis. Moreover, hypertrophic stress activates Src kinase-mediated Tyr359 phosphorylation and cytoplasmic accumulation of hnRNP L in CM. P-hnRNP L captures miR-574-3p and promotes exosome-mediated release of miR-574-3p and reduces cardiac fibroblasts (CF) proliferation by targeting CF Fam210a. Our central hypothesis is: in CM and CF, miR-574-Fam210a axis maintains optimal translation of mitochondrial-encoded genes and mitochondrial homeostasis, thereby limiting pathological cardiac hypertrophy and ventricular remodeling. We will test this hypothesis by pursuing 3 aims.
Aim 1. Elucidate the mechanism of guide strand miR-574-5p in preventing pathological cardiac hypertrophy and CM apoptosis.
Aim 2. Establish the role and mechanism of passenger strand miR-574-3p in antagonizing cardiac fibrosis.
Aim 3. Determine the function and mechanism of Fam210a in mitochondrial translational control and regulation of cardiac function.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and better understanding of the pathological mechanisms underlying CVD will improve preventive and therapeutic interventions. In this proposal, we will investigate the roles of both guide and passenger strands of a noncoding microRNA (miR-574) and their molecular target Fam210a in cardiac hypertrophy and heart failure. These studies will lead to identification of novel microRNA- based therapeutics and therapeutic targets for treatment of CVD.
