Novel anti-apoptotic mechanism of IL-1α/StAR in cardiac fibroblasts surviving myocardial infarction: role of plasma membrane cholesterol

In humans, myocardial infarction (MI) results in necrotic death of billion cardiomyocytes. In response to the event, onset of wound-healing process opens with indispensable inflammation triggered by the release of interleukin-1α (IL-1α) from the necrotic myocytes. IL-1α activates the border zone resident cardiac fibroblasts (CFs) that rapidly proliferate and differentiate to myofibroblasts responsible for scar formation preventing left ventricular deadly puncture.

We recently suggested (Razin et al., JMCC 155:125-137, 2021) that in order to survive the unavoidable stress associated with the inflammatory response, the CFs acquire anti-apoptotic resilience downstream of IL-1α induced upregulation of cardiac StAR, a protein normally known to be indispensable for steroid biosynthesis. Surprisingly, in the absence of cardiac steroidogenesis, cardiac StAR activity is anti-apoptotic, named stoptosis. We suggest that the mechanism of stoptosis requires StAR-dependent facilitation of plasma membrane (PM) cholesterol transport to intracellular destinations, probably including the mitochondria. This working hypothesis is based on ectopic expression of human StAR mutants showing that the PM cholesterol content is decreased by 50% in the presence of WT-StAR, while the steroidogenic-dead R182L StAR mutant cannot provide anti-apoptotic protection. Furthermore, using different fluorescently labeled cholesterol probes in primary rat CFs model, we demonstrate that endocytic entry of PM cholesterol is important for IL-1α/StAR stoptosis, while non-vesicular PM-to-ER cholesterol transfer to lipid droplets does not play any role in stoptosis.
Collectively, our observations suggest a novel anti-apoptotic mechanism depending on IL-1α/StAR controlled cholesterol homeostasis that probably explains the cardioprotective role of IL-1α after MI.