Apolipoprotein C3 drives adverse cardiac remodeling in ischemic heart failure.

Abstract

Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associated with the incidence of ischemic heart disease (IHD). However, the causal association between ApoC3 and IHD development is unclear. ApoC3 expression changes were assessed in plasma from IHF patients/healthy donors and cardiac tissue from rodent models. 10-week-old male human ApoC3 transgenic (ApoC3^Tg) mice, ApoC3 knockout (ApoC3^-/-) mice, ApoC3^-/- hamsters, and wild-type (WT) controls underwent left anterior descending coronary artery (LAD) ligation to establish IHF models 4 weeks post-MI. Echocardiography, biochemical assays, and histopathology were employed to investigate ApoC3's role and regulatory mechanisms in MI-induced IHF. Overexpression of human ApoC3 in ApoC3^Tg mice exacerbated IHF after MI surgery, characterized by cardiac hypertrophy with thinned ventricular wall thickness and decreased contractile function. Mechanistically, ApoC3 overexpression markedly upregulated its receptor TLR2 at the myocardial ischemic site, and activated the NF-κB pathway resulting in significant increases in inflammation, oxidative stress and apoptosis. Unfortunately, ApoC3 deficiency did not show an overt protective effect in mouse MI model. We subsequently introduced ApoC3^-/- hamsters and found that unlike mouse model, plasma HDL levels were markedly higher in ApoC3^-/-hamsters 4 weeks after surgery compared with WT hamsters cardiac remodeling and contractile function were significantly ameliorated with a reduction in TLR2 gene expression, eventually inhibiting inflammation, oxidative stress, and apoptosis in MI heart. ApoC3 overexpression could activate cardiac TLR2/NF-κB to trigger the inflammation, oxidation, and apoptosis pathways, finally aggravating IHF in mice. Inactivation of ApoC3 could significantly alleviate IHF in hamsters.