Apolipoprotein(a)-rich electronegative HDL accelerates vascular aging and atherosclerosis by inducing endothelial senescence.

The limited benefits of high-density lipoprotein (HDL)-targeted therapies have shifted the research focus to HDL quality; some HDL subtypes may be pro-atherogenic and may counteract the potential benefits of HDL therapies. This study investigated the pathological mechanism of H5, a highly electronegative and compositionally abnormal HDL subfraction characterized by impaired cholesterol efflux. We used anion-exchange chromatography to separate HDL into five subfractions (H1-H5) from blood from 131 asymptomatic individuals (95 with metabolic syndrome and 36 without [controls]). Plasma H5 levels were significantly elevated in individuals with cardiovascular disease risk compared to controls (4.0 ± 3.5% vs. 2.7 ± 1.0%, p = 0.024). Clinically, elevated H5 levels were independently associated with structural markers of subclinical carotid atherosclerosis, including increased intima-media thickness (IMT) and plaque burden, in an imaging cohort of 118 participants. Mechanistically, the triglyceride-rich H5 showed a distinct lipoproteome, enriched with apolipoproteins including Apo(a), ApoB, and ApoC3. H5 induced endothelial dysfunction through pathways associated with reactive oxygen species (ROS) accumulation, DNA damage, and cellular senescence in vitro and in vivo. The p53-p21 signaling axis was the central mediator of this H5-induced dysfunction. In mice, H5-induced dysfunction promoted a pro-atherogenic phenotype, mediated centrally by the p53-p21 signaling axis. Our study suggests that elevated Apo(a)-rich H5 levels are associated with atherosclerotic cardiovascular disease (ASCVD) risk and validates targeting HDL quality-specifically the H5 subfraction-as a novel therapeutic strategy.