Abstract P1087: Cd36-retinoic Acid-PPARδ Signaling Axis Modulates Cardiomyocytes’ Ability To Proliferate In Newly Born Neonatal Mice

• Published in: Circulation research 2023-08, Vol.133 (Suppl_1)
• Main Authors: Salama, Abou Bakr M, Abouleisa, Riham, Ou, Qinghui, Miller, Jessica, Dwenger, Marc, Gebreil, Ahmad, abdelhafez, Hania, Arai, Momo, Abdulwali, Sameeha, Almasry, yazan, Hill, Bradford G, Mohamed, Tamer
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.133.suppl_1.P1087

Abstract only Background: A pertinent question is why only a subset of fetal/neonatal cardiomyocytes (CMs) spontaneously proliferate. Using single-cell RNAseq, we previously showed a specific population of CMs that is more responsive to cell cycle induction (Abouleisa et al., Circulation, 2022). This population is characterized by expression of the transmembrane scavenger receptor, CD36 (fatty acid (FA) internalization receptor). Here, we aim to investigate the mechanism by which CD36 modulates CMs decision to enter into the cell cycle in neonatal P1 CMs. Methods and Results: Our single-cell RNAseq from primary CMs isolated from P1 hearts demonstrated that CD36 is specifically expressed in the spontaneously proliferating CMs and the CMs that respond to the exogenous cell cycle stimulation. CMs isolated from P1 CD36 knockout mice (CD36 KO ) showed 50% less proliferation capacity compared to WT P1 CMs. Interestingly, CD36 KO mice are born with smaller hearts which contain fewer CMs compared with their WT littermates. Furthermore, compared with WT littermates, which completely regenerate the heart apex following apical resection at P1, CD36 KO showed minimal regenerative capacity. Surprisingly, CD36 KO CMs didn’t show significant disruption in FA oxidation or glycolysis; however, bulk RNAseq data from the P1 CD36 KO hearts showed significant downregulation in the expression of retinoic acid (RA)-dependent signaling genes (e.g., PPARδ and RXRa) and a significant increase in PPARα expression. Confirming a causal role of CD36 in CM proliferation, we found that Cd36 is crucial in regulating the entry and interactions of RA or retinoid precursors in CMs. The CD36 + FACS-sorted CMs express significantly higher levels of PPARδ, RXRa, and FABP5 and lower levels of PPARα, which are crucial in regulating the response to cell proliferation. Furthermore, small molecule activation of PPARδ doubled cell cycle entry in P1 CMs and completely restored proliferation in CD36 KO CMs. These data suggest that CD36 is essential to prime CMs proliferation during development by regulating RA/PPARδ/RXR transcriptional signaling. Conclusions: These findings suggest that the CD36-RA-PPARδ signaling axis modulates the CMs’ ability of P1 to spontaneously enter the cell cycle.