Abstract
Introduction: Following an ischemic injury, the persistence of cardiac myofibroblast (myo-FBs) contributes to fibrosis and adverse myocardial remodeling, especially if myoFBs remain active in otherwise healthy areas of the heart, away from the site of injury. The exact mechanisms underlying myo-FB activation and persistence remain unknown. Hypothesis: Since recent genome-wide association (GWA) studies have identified a significant association between gain-of-function mutations in genes encoding for inositol 1,4,5-trisphosphate receptors (IP3Rs) and ischemic heart disease, we hypothesized that IP3Rs could be involved in post-ischemic cardiac fibrosis. Methods: We applied an established model of ischemia/reperfusion (I/R) to a newly generated triple KO mouse specifically lacking all isoforms of IP3Rs in cardiac myo-FBs, in order to avoid compensatory responses. Results: After I/R, IP3Rs level is not changed in the scar area, whereas it is markedly upregulated in the remote regions. Compared to control littermates, KO mice display a reduced interstitial fibrosis and an attenuated myocardial dysfunction following I/R. Mechanistically, we show for the first time that IP3Rs modulate apoptosis in myo-FBs following ischemic injury in a calcium-independent manner, i.e. by directly sequestrating the pro-apoptotic factor PUMA (p53 upregulated modulator of apoptosis), thereby favoring the detrimental myoFBs persistence in the remote areas. Strikingly, these results were confirmed in human cardiac specimens from patients with heart failure, as well as in vitro in human FBs, in which IP3Rs are shown to regulate cell proliferation and migration. Conclusions: Our findings indicate that the IP3R-PUMA interaction selectively regulate the activation of cardiac myo-FBs located in the regions remote from the ischemic injury.
Published Version
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