Abstract 456: High Fat Diet-Induced Atherosclerosis-Driven Myocardial Infarction: Role of Cardiac Long Noncoding RNAs in Triiodo-L-Thyronine-Mediated Protection

Abstract

Novel mechanisms associated with therapeutically safe thyroid hormone (TH) therapy are emerging. We have shown that oral triiodo-L-thyronine (T3) offers safe cardioprotection in coronary ligation myocardial infarction (MI), ligation ischemia-reperfusion injury, diabetic cardiomyopathy, etc. via restoration of gene expression. However, safe therapeutic effects following atherosclerosis-driven MI and role of long noncoding RNAs (lncRNAs) is unknown. We employed a mouse model of scavenger receptor B1 knockout with hypomorphic apolipoprotein E. Young adult heterozygote littermates served as controls and all mice received high fat (HF) diet for one month. Along with HF diet, a cohort of homozygotes (HypoE) received therapeutic dose of T3 (5.5 μg/kg/d) in drinking water ad libitum. In HypoE mice, Paigen HF diet induced interstitial fibrotic MI with severe hypertrophic (Heart wt./Body wt., HW/BW: control:4.6±0.14; HypoE:12.9±0.75; p<0.0001) heart failure, depressed left ventricular (LV) contractility, increased end-diastolic pressure, myocyte disarray/loss, vacuolization and inflammatory cell infiltration. Aortic root showed atheromatous lipid deposits and median survival time was 26 days. Cholate-free paigen HF diet, used to achieve more gradual transition showed moderate hypertrophy (HW/BW: control:4.9±0.1; HypoE:7.9±0.95; ; p<0.01), decreased LV contractility, increasing atrial effective refractory period with a median survival of 41.5 days. Other changes include decreased serum thyroxine, increased serum cholesterol, significant splenomegaly and alterations in real-time gene expression of numerous cardiac lncRNAs and limited serum lncRNAs involved in inflammatory and immune responses (>2-fold; p<0.05). Oral T3 therapy with cholate-free diet partially restored LV contractility, atrial refractory period and cardiac lncRNAs without significantly affecting serum lncRNAs. These were accompanied by expected feedback inhibition of thyroxine without negatively impacting hypertrophy or heart rate. This is the first study to show a novel role of lncRNAs in TH-mediated cardioprotection. It also demonstrates possibility of safe preventive T3 therapy in a clinically relevant early coronary artery disease model.