As far as we know, the present study demonstrated for the first time that there was an independent relationship between ANGPTL3 and CAD. The major finding was that ANGPTL3 levels were significantly elevated in patients with CAD. In addition, multivariate logistic regression analysis showed that ANGPTL3 was still independently associated with the presence and severity of CAD.
Dyslipidemia, characterized by increased plasma levels of low density lipoprotein cholesterol (LDL-C) and triglycerides (TG), has long been identified as a core pathogenic aetiology of CAD[19]Ldl-c is known as the most important risk factor for CAD. Although most people use statins, ezetimibe, and PCSK9 inhibitors to reduce LDL-C, patients with mixed dyslipidemia still have a high risk of cardiovascular events. For example, patients treated with statins with HDL-c levels < 39 mg/dL had an increased risk of ACS compared with patients with HDL-C levels > 55 mg/dL[20].Although there is no evidence that TG directly plays an atherogenic role, the atherogenic effect of triglyceride-rich lipoprotein and its residues has been confirmed [21, 22].
Recently, ANGPTL3 has been shown to inhibit LPL activity and participate in the regulation of lipoprotein metabolism, so ANGPTL3 is considered a promising pharmacological target for the treatment of dyslipidemia[23]. ANGPTL3 is a 70 kDa-secreted protein mainly expressed in the liver, both during embryonic development and in the adult stage[24].ANGPTL3 belongs to the angiopoietin-like proteins family and is composed of N-terminal coiled helix domains involved in binding and inhibition of LPL (lipoprotein lipase) and EL (endothelial lipase) and C-terminal fibrin primitive domains that mediate ANGPTL3's angiogenic properties[25].
Under normal conditions, ANGPTL3 mainly maintains physiological levels of plasma TG, in addition to regulating plasma LDL cholesterol levels[26]. The suppression of lipoprotein lipase (LPL), liver lipase (HL), and endothelial lipase, which inhibits the lipolysis of plasma lipoprotein TG and phospholipid, is the principal mechanism of ANGPTL3's influence on lipid levels[27].
The inhibitory effect of ANGPTL3 on LPL can be enhanced by ANGPTL8[28]. Increased plasma TG levels caused by ANGPTL3 overexpression may be reduced in the absence of ANGPTL8. ANGPTL3 is activated by ANGPTL8, which forms a functional ANGPTL3/8 complex upon ingestion, boosting the inhibition of LPL activity mediated by ANGPTL3[29, 30].As a result, ANGPTL3 is seen as a possible pharmaceutical target for the therapy of dyslipidemia[26, 31], however the exact mechanisms are unknown.
ANGPTL3 can affect the clearance of triglyceride-rich lipoproteins and increase plasma triglyceride levels by reducing LPL and liver lipase activities. Therefore, inhibition of ANGPTL3 can reduce lipid levels by enhancing LPL activity and promoting lipoprotein cleavage and clearance. According to this hypothesis, ANGPTL3 regulates lipid levels in vivo, with loss of ANGPTL3 leading to global hypolipemia and overexpression of ANGPTL3 leading to elevated lipid concentrations[32].
In the DiscovEHR study, Participants with heterozygous loss-of-function mutations in ANGPTL3 had significantly lower serum levels of triglycerides(27%),HDL-C(4%) and LDL-C(9%), compared to those who did not have these variants. Changes in plasma lipid levels in ANGPTL3 loss-of-function variant carriers vs. noncarriers are linked to a 40% reduction in the risk of atherosclerotic cardiovascular disease[33].
According to human genetic studies, several loci near the ANGPTL3 gene 1p31 were repeatably correlated with triglyceride concentrations[34].In a subsequent study, exome sequencing in the protein-coding regions of the genomes of two family members with combined hypolipidemia and found that two participants were nonsense mutations in ANGPTL3.a condition characterized by low fasting plasma triglyceride levels, low levels of LDL-C and HDL-C[35].
Our research shows that ANGPTL3 level was significantly positively correlated with TC, TG and LDL-C, and negatively correlated with HDL-C. In addition, our study also showed that ANGPTL3 level was significantly positively correlated with HCY level, and the relationship between ANGPTL3 level and HCY is still unclear.
Stitziel et al. Showed that 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque.Heterozygous carriers of ANGPTL3 loss-of-function mutations had a 17 percent drop in circulating triglycerides and a 12 percent reduction in low-density lipoprotein cholesterol when compared to those without the mutation. Carrier status was linked to a 34% lower risk of coronary artery disease. Individuals in the lowest tertile of circulating ANGPTL3 concentrations had a lower risk of MI than those in the highest tertile.[36].
The reduced risk of ASCVD in carriers of ANGPTL3 dysfunction makes ANGPTL3 a very attractive lipid-lowering pharmacological target..Evinacumab, an all-human monoclonal antibody that binds specifically to ANGPTL3, has been developed and shown to reverse ANGPTL3-mediated inhibition of LPL activity in vitro and in vivo. In preclinical animal studies, evinacumab increased LPL activity after heparin and reduced plasma TG, LDL-C, and HDL-C levels in normal and hyperlipidemia mice[37]. Evinacumab significantly reduced atherosclerotic lesions and plasma TG, VLDL, and total cholesterol levels in APOE*3 Leiden CETP mice with hypercholesterolemia.[38]
Many studies have attempted to explore the association between ANGPTL3 level and CAD. In our study, we found that ANGPTL3 level was an independent risk factor for CAD. We also conducted multi-factor linear regression analysis between ANGPTL3 level and Gensini score in CAD patients, and the results showed that ANGPTL3 level was significantly positively correlated with Gensini score, indicating that ANGPTL3 level was significantly positively correlated with coronary artery severity in CAD patients.