A novel association between TGFb1 and ADAMTS4 in coronary artery disease: A new potential mechanism in the progression of atherosclerosis and diabetes

Abstract

Objective:Coronary artery disease is characterized by atherosclerosis in the vessel wall. Recently, it has been thought that increasing LDL-binding capacity of subendothelial proteoglycan fragments that are formed by protease activity can be responsible for the initiation of atherosclerosis. ADAMTS4 is a member of the versican-degrading proteinases. In vitro studies demonstrated that TGFβ inhibits the expression of ADAMTS4 in macrophages. In this study, we aimed to investigate the role and association between TGFβ1 and ADAMTS4 in coronary artery disease.Methods:A total of 84 cases with atheroma plaque and 72 controls without plaque were analyzed. The severity of disease was determined by Gensini score. TGFβ1 gene polymorphisms were genotyped by the PCR-RFLP method. TGFβ1 and ADAMTS4 serum levels were measured by ELISA method. Statistical analyses of genotypes and their relationship with serum levels were performed by chi-square, student t test and ANOVA.Results:ADAMTS4 levels were higher in cases compared with controls (p<0.05). In the patient group, ADAMTS4 levels were higher than in controls and correlated with TGFβ1 serum levels (r=0.29; p<0.05) and severity of disease (r=0.20; p<0.05). The TGFβ1 gene CCA haplotype was associated with 3.3-fold increase in coronary artery disease (OR=3.26 95% CI 1.22-8.68; p<0.05). Unexpectedly, ADAMTS4 serum levels were also higher in diabetic cases (p=0.05).Conclusion:This study has demonstrated that ADAMTS4 may be responsible for the pathogenesis of atherosclerosis. This is the first report about the association between ADAMTS4 and TGFβ1 serum levels in the progression of atherosclerosis in CAD. Furthermore, it is seen that TGFβ1 haplotype can cause a genetic susceptibility to CAD in the Turkish population. To our knowledge, this is also the first report suggesting higher serum ADAMTS4 levels in diabetic patients.

Transforming Growth Factor-β Protects against Inflammation-Related Atherosclerosis in South African CKD Patients

“…There is no consensus about the role of TGF- β 1 in the process of atherosclerosis and restenosis. Some studies have reported an association between elevated TGF- β 1 levels and vascular restenosis lesions [ 30 , 44 ]. In contrast, other authors have showed that decreased expression of TGF- β 1 contributes to progression of atherosclerosis [ 10 , 22 , 23 ].…”

The prognostic value of inflammatory and vascular endothelial dysfunction biomarkers in microvascular and macrovascular complications in type 1 diabetes

“…Although TGF-β1 was thought to be a pro-atherogenic factor for many years, recent studies have shown that, in reality, it seems to limit the atherosclerosis by modulating a number of processes such as inflammatory response or the accumulation of lipids in the vessel wall [57,58]. The effect of increased TGFβ1 levels in diabetics on atherogenesis is not fully elucidated, and further investigations are necessary.…”

Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE−/− mice

“…ADAMTS4 is also elevated in human plasma of patients with both stable coronary artery diseases (CAD) as well as acute coronary syndromes (ACS) 15 . High plasma levels of ADAMTS4 is also associated with the severity of CADs in patients 16 17 . More importantly, using a tandem stenosis induced carotid artery plaque rupture model in ApoE −/− mice, potential pathogenic factors that are upregulated in ruptured plaques were identified.…”