Role of novel RNA binding protein LARP6 in alcoholic cardiomyopathy

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Chronic excessive alcohol consumption can cause cardiac dysfunction and dilation, clinically termed alcoholic cardiomyopathy (AC). While chronic alcohol abuse alone causes AC, clinical evidence indicates that alcohol can exacerbate cardiac dysfunction resulting from other causes of cardiac injury or stress. Alcohol abuse also increases the risk of hypertension and heart failure, with as many as one third of all dilated cardiomyopathies attributed to AC. The development of cardiac fibrosis appears to be a key mechanism of AC dysfunction, as fibrosis impairs ventricular filling and impedes cardiomyocyte contraction. LARP6 is an RNA binding protein that upregulates collagen I expression post-transcriptionally by binding to the 5’SL structure and stabilizing the mRNA. Using a genetic knock-in mouse with modified 5’SL that prevents LARP6 binding, others have shown significantly decreased overall collagen expression and deposition in bile duct ligation-induced hepatic fibrosis. Stefanovic and colleagues discovered a drug-like compound, C9, that blocks the interaction between LARP6 and collagen I. They demonstrated that C9 inhibits collagen I expression in cultured hepatic stellate cells and prevented the development of fibrosis in animal models of hepatic fibrosis. Our preliminary studies indicate that both the knock-in 5’SL mouse and C9-treated wildtype mice are resistant to the development of cardiac fibrosis and dysfunction in response to chronic isoproterenol infusion. In the current proposal, using this unique genetic model and C9 compound, we will determine the role of LARP6 in AC. Our long-term goal is to identify the mechanisms responsible for alcohol-induced cardiac injury, which can then be targeted for clinical benefit. We hypothesize that blocking the interaction between LARP6 and collagen I mRNA significantly blunts cardiac remodeling (fibrosis and hypertrophy) and contractile dysfunction in a preclinical model of AC. Using the well- established NIAAA chronic+binge alcohol mouse model, we propose the following specific aims: Aim 1 determines whether blocking the interaction between LARP6 and collagen I in the 5’SL knock-in mice blunts alcohol abuse-induced adverse cardiac remodeling and dysfunction. We utilize integrated and systematic in vivo and in vitro approaches focused on ethanol-induced cardiac dysfunction, inflammation, oxidative stress, apoptosis, fibroblast activation, and fibrosis. Aim 2 investigates whether pharmacological blockade of LARP6 and collagen I interaction by the small molecule inhibitor C9 inhibits and/or reverses chronic alcohol abuse- induced cardiomyopathy. In this interventional approach, we will determine the therapeutic potential of C9 both prophylactically and therapeutically using the NIAAA model of AC. Outcome measures include cardiac diastolic and systolic function, ventricular chamber dimensions, collagen typing and cross-linking, inflammation, oxidative stress, and interstitial fibrosis. Our proposed genetic and interventional studies will determine if blocking LARP6 and collagen I interaction can blunt chronic alcohol-induced cardiomyopathy and serve as a potential novel therapeutic target for the treatment of clinical AC.