Apolipoprotein A (ApoA) in Cardiovascular Disorders: Connections and Insights

Apolipoprotein A (ApoA) family members-ApoA-I, ApoA-II, ApoA-IV, and ApoA-V-play important roles in the vasculature that extend beyond lipid transport to regulate lipid-immune crosstalk, vascular homeostasis, and triglyceride metabolism. ApoA-I mediates reverse cholesterol transport, yet its cardioprotective capacity depends on functional integrity rather than HDL-cholesterol levels alone. ApoA-II, ApoA-IV, and ApoA-V exhibit context-dependent roles ranging from enhancing cholesterol efflux and triglyceride clearance to modulating inflammation, oxidative stress, endothelial activation, and thrombosis. Post-translational modifications such as oxidation, glycation, and citrullination within inflammatory milieus can convert protective ApoA proteins into dysfunctional or proinflammatory mediators. Genetic variations within APOA gene clusters have clarified the causal contribution of triglyceride-rich lipoproteins to atherosclerotic risk, shifting emphasis from HDL quantity toward lipoprotein quality and remnant cholesterol burden. In this comprehensive review, we synthesize structural, genetic, mechanistic, and clinical evidence to evaluate the position of the 4 ApoA proteins as context-dependent modulators of cardiovascular disease. We highlight the dualistic nature of their actions and examine failed clinical trials of ApoA-I infusions and mimetic peptides. We conclude by discussing how shifting focus from HDL quantity toward lipoprotein quality and preservation of ApoA functional integrity may inform more precise approaches to residual cardiovascular risk and triglyceride-driven atherogenesis.