Interleukin-1α activates expression of steroidogenic acute regulatory protein (StAR) required for survival in post infarction cardiac fibroblasts

Talya Razin ¹ Naomi Melamed-Book ² Jasmin Argaman ¹ Iris Galin ¹ Eli Anuka ¹ Nili Naftali-Shani ^3,4 Michal Kandel-Kfir ⁵ Yehuda Kamari ⁵ Jonathan Leor ^3,4 Joseph Orly ¹

¹Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, the Hebrew University of Jerusalem, Israel
²The Bio-Imaging Unit, The Alexander Silberman Institute of Life Sciences, the Hebrew University of Jerusalem, Israel
³Neufeld Cardiac Research Institute, Sackler Faculty of Medicine, Tel-Aviv University, Israel
⁴Tamman Cardiovascular Research Institute, Sheba Center of Regenerative Medicine, Stem Cells and Tissue Engineering, Sheba Medical Center, Israel
⁵The Bert W. Strassburger Lipid Center, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel

Release of proinflammatory IL-1α from necrotic myocytes injured by myocardial infarction (MI) is the proximal alarming signal triggering post-ischemic innate inflammation by activating border zone (BZ) resident fibroblasts to undergo proliferation and differentiate into active myofibroblasts. The myofibroblasts drive tissue remodeling by forming fibrotic scar to prevent left ventricular wall rupture.

Important question remained unaddressed is how the BZ fibroblasts survive during the proapoptotic inflammatory response. We suggest that antiapoptotic stability of the fibroblasts is mediated by the unexpected ability of these cells to express StAR, a protein normally required for steroid hormones biosynthesis. We have shown that cardiac StAR is not steroidogenic and therefore StAR should have an alternative activity.

Work with primary cardiac fibroblasts culture revealed that Star gene products are exclusively upregulated by IL-1α, a notion further confirmed in lack of StAR expression in IL-1α deficient mice. Furthermore, IL-1α treatment of cardiac fibroblast culture turned the cells resistant to apoptosis when exposed to the strong apoptogen, cisplatin. This anti-apoptotic impact of IL-1α was reversed upon StAR knockdown by siRNA suggesting that StAR presence is necessary for the cells survival. In vivo, MI in IL-1α deficient mice resulted in a 65-70% reduction of fibroblasts/myofibroblasts cell markers and nearly 3-fold increase of cell death, which suggests a substantial decline of fibroblasts survival in the LV free wall of the IL-1α/StAR deficient heart.

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 to ensure proper tissue remodeling after MI.