Urna Kansakar, PhD: No financial relationships to disclose
Background: Inositol 1,4,5-trisphosphate receptors (ITP3Rs, a.k.a. IP3Rs) are intracellular calcium (Ca2+) release channels located on the endoplasmic reticulum (ER). While the role of IP3Rs in cardiomyocytes has been previously investigated, especially in the context of hypertrophy and arrhythmias, their exact function in the activation of cardiac fibroblasts (FBs) has not been determined. The main goal of this project is to understand the functional role of IP3Rs in the activation of cardiac fibroblasts (FBs) and their transition to myoFBs after ischemia/reperfusion (I/R). We hypothesize that FB IP3Rs participate in the phenoconversion of FBs into activated myoFBs and induce persistent cardiac fibrosis in cardiac I/R.
METHODS AND RESULTS: We demonstrated that all IP3R isoforms are upregulated in FBs following ischemic injury both at mRNA and protein level. Since mitochondrial bioenergetic pathways have been recently proposed as key players in myoFB phenoconversion, we tested mitochondrial metabolism in FBs isolated from remote regions and scar areas. We found an altered mitochondrial metabolism, which was significantly shifted toward aerobic glycolysis in FBs from remote areas. These alterations, not detected in FBs isolated from the infarct area, were partially rescued by IP3Rs ablation. Moreover, genome-wide association studies (GWAS) revealed a significant association between IP3Rs and ischemic heart disease. However, definitive functional studies examining the mechanistic role of IP3Rs in cardiac fibrosis in vivo are missing. Using a Cre/lox recombination technique, we generated a novel cardiac myoFB-specific IP3R knockout (IP3RKO) mouse model in which IP3Rs are ablated in activated cardiac myoFBs. This model provides an exquisite tool to evaluate the functional contribution of IP3R to cardiac fibrosis and allows us to overcome the difficulties encountered following the knockdown or KO of a single IP3R gene. Our preliminary studies show that following myocardial infarction (MI), IP3RKO mice display a significantly reduced fibrosis and attenuated myocardial dysfunction compared with control IP3RCre and IP3Rflox littermates.
Conclusion: Our results provide the first assessment of the functional role of IP3R in post-MI cardiac FBs using a specific Cre/lox KO model and identify innovative therapeutic strategies that specifically target excessive post-ischemic cardiac fibrosis.
