Abstract P2104: Branched-chain Amino Acids Are Required For Acquisition Of The Cardiac Myofibroblast Phenotype

Abstract

Introduction: Branched-chain amino acids (BCAAs) are critical mediators of anabolic signaling and are essential for cell growth. Findings in both animals and humans indicate that intra-cardiac BCAA levels are markedly elevated in the myocardium after infarction. Nevertheless, it remains unclear how BCAAs contribute to processes involved in post-infarction cardiac remodeling, such as fibrosis. The goals of these studies were to evaluate whether BCAAs can regulate collagen production and facilitate myofibroblast transdifferentiation. Methods and Results: To determine how profibrogenic stimuli influence genes critical for BCAA uptake and catabolism, we performed bulk RNA sequencing on fibroblasts isolated from sham and post-infarcted hearts as well as from naïve fibroblasts treated with TGFβ. Compared with fibroblasts from sham hearts, fibroblasts from post-infarcted hearts had higher expression of BCAA transporters ( Slc7a8 , Slc3a2 , Slc38a1 , Slc1a5 ), lower levels of the inhibitory kinase Bckdk , and higher levels of Bckdh complex constituents ( Dbt, Dld ; n=3–6/group;,q<0.05). Similarly, TGFβ elevated Slc3a and Slc38a1 as well as the BCAA catabolic gene, Bcat1 (n=3/group; q<0.05). Culture of cardiac fibroblasts in BCAA-free medium completely prevented TGFβ-induced Col1a1 and periostin upregulation and markedly diminished α-smooth muscle actin abundance (n=3/group; p<0.05). Conclusion: In cardiac fibroblasts, profibrogenic stimuli increase the expression of genes involved in BCAA uptake and catabolism. BCAA availability significantly impacts fibroblast activation by regulating collagen synthesis and myofibroblast transdifferentiation. Ongoing studies will elucidate whether BCAA catabolism contributes to myofibroblast activation and whether lower dietary BCAA levels influence cardiac remodeling after myocardial infarction.