Interleukin-1α Induced Expression of Steroidogenic Acute Regulatory Protein (StAR) Facilitates Fibroblasts Survival Following Myocardial Infarction

Introduction: Release of proinflammatory interleukin-1α (IL-1α) from necrotic myocytes injured by myocardial infarction (MI) is the proximal alarming signal that triggers post-ischemic innate inflammation by activating resident fibroblasts in the infarct border zone (BZ) tissue. Recent studies have shown that while the inflammatory phase is in progress, resident fibroblasts of the infarct BZ undergo proliferation, populate the infarct vacant space and differentiate into active myofibroblasts. The myofibroblasts drive tissue remodeling by deposition of extracellular matrix to form fibrotic scar replacing lost cardiomyocytes and thereby prevent left ventricular wall rupture.

Important questions remained unaddressed are how the tissue remodeling BZ fibroblasts survive during the inflammatory response known to locally generate proapoptotic stress milieu. We suggest that a key player for understanding the BZ fibroblasts robustness is their unexpected ability to express the steroidogenic acute regulatory protein (StAR), a long known protein indispensable for steroid hormones biosynthesis. We have shown that cardiac StAR is not associated with steroidogenesis.. We therefore hypothesized that the cardiac StAR should have a new alternative activity.

Methods and Results: Biochemical and histochemical approaches showed that StAR expression is transient and lasts during the inflammatory response after MI. IHC evidenced searching for co-expression of StAR with cell markers such as PDGFRα and periostin, revealed that StAR appears in interstitial and adventitial fibroblasts/myofibroblasts residents of the infarct BZ. Work with primary culture of rat cardiac fibroblasts revealed that Star gene products are specifically upregulated by the proinflammatory IL-1α, a notion further confirmed after MI in IL-1a deficient mouse model (IL-1α KO). Furthermore, IL-1α treatment of the cardiac fibroblasts in culture turns the cells markedly resistant to induced apoptosis by a strong apoptogen, cisplatin. This anti-apoptotic impact of IL-1α activation of the fibroblasts is strictly dependent on IL-1α induction of StAR expression. In vivo, myocardial infarction in IL-1α deficient mice resulted in 65-70% reduction of Postn, PDGFRα and proliferating cells nuclear antigen (PCNA) expression, which suggests a 70% decline of replicating fibroblasts in the LV free wall. Further experiments are expected to unravel if inflammation related fibroblasts cell death underlies the observed loss of these cells in the IL-1α/StAR deprived KO mice.

Conclusions: These findings identify a new mechanism by which IL-1α confers anti-apoptotic protection mediated by StAR expression in fibroblasts/myofibroblasts expected to survive during the inflammatory response in order to ensure proper tissue remodeling after MI.