Abstract Body: Introduction/Background:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a mediator of cardiovascular disease beyond its established role in cholesterol metabolism. Emerging evidence indicates that PCSK9 can also be expressed in cardiac tissues under pathological conditions such as oxidative stress and inflammation. PCSK9 has also been reported to interact with CD36, a key receptor involved in long-chain fatty acid uptake and lipid metabolism. However, the role of CD36 in the heart during ischemia/reperfusion (I/R) injury remains poorly defined. CD36 has been implicated in cAMP/PKA signaling in cardiomyocytes.
Research Questions/Hypothesis:
Myocardial ischemia increases PCSK9 expression in the heart. However, the mechanisms by which PCSK9 contributes to cardiomyocyte injury remain unclear. We hypothesized that PCSK9 exacerbates cardiomyocyte death through CD36-dependent modulation of cAMP/PKA signaling and downstream activity.
Goals/Aims:
This study aimed to determine the role of PCSK9 during I/R injury and to elucidate the signaling mechanisms regulating cardiomyocyte survival.
Methods/Approach:
To investigate the role of PCSK9 in cardiac injury, mechanistic studies were performed in HL-1 mouse cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). PCSK9 was overexpressed in HL-1 cells using a Flag-tagged PCSK9 plasmid and hiPSC-CMs using adenoviral delivery. Cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) conditions to assess cell viability, signaling pathways, and calcium homeostasis. The interaction between PCSK9 and CD36 was examined by co-immunoprecipitation.
Results/Data:
The results showed that the overexpression of PCSK9 increased cardiomyocyte apoptosis under H/R conditions. Mechanistically, PCSK9 directly interacted with CD36 and reduced cyclic AMP levels, leading to suppression of protein kinase A (PKA) signaling and reduced β-catenin phosphorylation at Ser675 in cardiomyocytes. Consistently, increased apoptosis was observed in HL-1 cells and hiPSC-CMs treated with exogenous PCSK9. In addition, PCSK9 overexpression disrupted intracellular calcium homeostasis in hiPSC-CMs under normoxic and H/R conditions.
Conclusion(s):
These findings suggest that PCSK9 contributes to cardiomyocyte injury through modulation of CD36–associated signaling pathways. Targeting PCSK9-mediated signaling may represent a potential therapeutic strategy for ischemic cardiomyopathy.