Repurposing the gastroprotective agent geranylgeranylacetone for atherosclerosis: a novel role of the HSP22-Nrf2-mitochondrial axis.

Abstract

Mitochondrial dysfunction is a pivotal driver of vascular endothelial injury and atherogenesis. This study aimed to evaluate the therapeutic potential of geranylgeranylacetone (GGA), a clinically established gastroprotective agent, in atherosclerosis and to explore the underlying molecular mechanisms. Apolipoprotein E-deficient (ApoE-/-) mice with genetic heat shock protein 22 (HSP22) overexpression or deficiency were used to investigate the vascular effects of HSP22 in vivo. In vitro, human umbilical vein endothelial cells (HUVECs) were challenged with oxidized low-density lipoprotein (Ox-LDL). GGA treatment reduced atherosclerotic plaque burden and circulating total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels, while improving systemic oxidative and inflammatory status and increasing HSP22 expression in the aortic wall. HSP22 overexpression was associated with reduced plaque burden and improved vascular and mitochondrial homeostasis without substantially altering serum lipid profiles. In Ox-LDL-treated HUVECs, HSP22 overexpression preserved cell viability, mitochondrial bioenergetics, and mitochondrial network architecture, accompanied by increased expression of optic atrophy protein 1 (OPA1) and Mitofusin 2 (Mfn2) and reduced mitochondrial reactive oxygen species (mtROS) accumulation. Factorial analysis further demonstrated significant interactions between HSP22 silencing and GGA treatment for endothelial viability and selected vascular and mitochondrial markers. Mechanistically, HSP22 promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation, while pharmacological Nrf2 inhibition attenuated the protective effects of both HSP22 and GGA. Collectively, these findings suggest that GGA exerts anti-atherosclerotic effects through complementary systemic lipid-lowering and HSP22-associated vascular protective mechanisms, with Nrf2 contributing to the latter. GGA may therefore represent a potential drug-repurposing candidate for atherosclerosis warranting further investigation.