Smooth Muscle Overexpression of PGC1α Attenuates Atherosclerosis in Rabbits.

Rationale: Targeting vascular smooth muscle cell (VSMC) phenotypic switching is a promising therapeutic approach for atherosclerosis (AS). Dysregulation of PGC1α, a key regulator of cellular energy metabolism, has been implicated in the pathogenesis of AS, yet its role in AS remains controversial. Objective: The current study aimed to determine whether and how PGC1α in VSMCs regulates AS progression. Methods and Results: We generated transgenic (Tg) rabbits with SMC-specific PGC1α overexpression and showed that these rabbits developed significantly less aortic AS than their non-Tg littermates after high-cholesterol diet (HCD) feeding, while total plasma cholesterol levels were similar. As indicated by the restored expression of VSMC differentiation marker genes, the HCD-induced phenotypic switching in the aortic media was largely reversed in Tg rabbits, accompanied by decreased levels of synthetic phenotype genes, proinflammatory cytokines, adhesion molecules, macrophage infiltration, matrix metalloproteinases (MMPs), reactive oxygen species (ROS) production and senescence. Ex vivo studies further showed that VSMC-specific PGC1α overexpression markedly suppressed the promotive effect of HCD feeding on the association of serum response factor (SRF) with ELK1, a ternary complex factor (TCF) that acts as a myogenic repressor in VSMCs, thereby preserving the VSMC contractile phenotype. Furthermore, knockdown of PGC1α remarkably increased extracellular signal-regulated kinase (ERK)1/2-ELK-1 signaling, which promoted phenotypic switching and proliferation of cultured rabbit VSMCs. In addition, we showed that PGC1α can regulate EGFR-ERK1/2 MAP kinase signaling via modulating PPARγ activity in RVSMCs. Finally, we showed that these beneficial results of SMC-specific PGC1α overexpression can be extrapolated from rabbits to human VSMCs and clinical settings. Conclusions: We demonstrated a critical role of PGC1α in maintaining the contractile phenotype of VSMCs and highlighted the therapeutic potential of PGC1α for AS.