Abstract MP150: Inositol 1,4,5-trisphosphate Receptors Selectively Regulate Detrimental Cardiac Fibrosis by Modulating ER-phagy

Abstract

Background: Therapeutic strategies that specifically target excessive post-ischemic cardiac fibrosis are lacking but desperately needed; thus, it is critical to understand the molecular mechanisms underlying these processes. Genome-wide association studies have revealed an association between inositol 1,4,5-trisphosphate receptors (IP3Rs) and ischemic heart disease. However, experimental studies examining the exact role of IP3Rs in post-ischemic cardiac fibrosis are missing. Aim: We hypothesize that IP3Rs play a key role in the regulation of cardiac myofibroblasts (myoFBs) in healing the infarcted heart after myocardial infarction (MI). Methods: We performed an integrated set of in vivo, ex vivo , and in vitro experiments aiming at identifying the functional role of cardiac myoFB IP3Rs in post-ischemic cardiac remodeling. We generated cardiac myo-FB-specific Triple IP3R knock-out (IP3R TKO ) mice ( Cre/lox recombination technique; Promoter: Periostin ), allowing us to overcome the difficulties encountered following the KO or KD of a single (of the three existent) IP3Rs, a strategy that has been shown to induce compensatory upregulation of the other isoforms. Results: After MI, IP3Rs are significantly upregulated in myoFBs of the remote regions but not in the scar area. IP3R TKO mice display a significantly reduced interstitial cardiac fibrosis and a markedly attenuated myocardial dysfunction following MI compared with control IP3R flox or Periostin Cre littermates. Moreover, FBs lacking IP3Rs exhibit significantly reduced migratory and secretory capacities, a finding confirmed both in murine and human FBs. Mechanistically, we show that IP3Rs modulate endoplasmic reticulum autophagy (ER-phagy) in primary isolated myoFBs following ischemic injury. Conclusions: Taken together, our findings indicate for the first time that IP3Rs are essential for the regulation of post-ischemic cardiac fibrosis.