Poldip2 negatively regulates matrix synthesis at focal adhesions

Atherosclerotic cardiovascular disease is a major cause of death worldwide [ [1] Murray C.J. Lopez A.D. Measuring the global burden of disease. N. Engl. J. Med. 2013; 369: 448-457 Crossref PubMed Scopus (1201) Google Scholar ]. Atherosclerosis is classified by several lesion types, including intimal thickening (smooth muscle cell accumulation), xanthoma (accumulation of foam cells), pathological intimal thickening (accumulation of lipid pools), fibroatheroma (necrotic core), and fibrocalcific plaque [ 2 Stary H.C. Natural history and histological classification of atherosclerotic lesions: an update. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1177-1178 Crossref PubMed Scopus (589) Google Scholar , 3 Virmani R. Kolodgie F.D. Burke A.P. Farb A. Schwartz S.M. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1262-1275 Crossref PubMed Scopus (3209) Google Scholar ]. Among the advanced lesion types, unstable plaque (vulnerable plaque), which has a tendency to rupture, features rich lipid deposition [ [4] Lee R.T. Libby P. The unstable atheroma. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1859-1867 Crossref PubMed Scopus (504) Google Scholar ], a thin fibrous cap [ [5] Burke A.P. Farb A. Malcom G.T. Liang Y.H. Smialek J. Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N. Engl. J. Med. 1997; 336: 1276-1282 Crossref PubMed Scopus (1460) Google Scholar ], infiltration of inflammatory cells, including macrophages [ [6] Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001; 104: 365-372 Crossref PubMed Scopus (1323) Google Scholar ], positive remodeling (outward remodeling) of vessels, and increased neovascularization. Disruption of plaque causes athero-thrombosis due to exposure of the underlying prothrombotic artery wall to platelets and coagulation factors [ [7] Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868-874 Crossref PubMed Scopus (6924) Google Scholar ], thereby leading to sudden artery occlusion. This disrupted plaque is associated with about 70% of the thrombi responsible for acute coronary syndromes [ [8] Falk E. Shah P.K. Fuster V. Coronary plaque disruption. Circulation. 1995; 92: 657-671 Crossref PubMed Scopus (3129) Google Scholar ]. Several critical factors contribute to the ultimate rupture of a fibrous cap, including mechanical stresses, which develop in the thin fibrous cap, particularly at the border zone between the atherosclerotic and normal regions (the "shoulder" region), and thin-cap fibroatheromas (TCFAs: cap thickness < 65 μm), which are associated with a high risk of plaque rupture [ [3] Virmani R. Kolodgie F.D. Burke A.P. Farb A. Schwartz S.M. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1262-1275 Crossref PubMed Scopus (3209) Google Scholar ]. The fibrous cap mainly consists of extracellular matrix (ECM) proteins such as collagen I. Although stabilization of unstable plaque by increasing the thickness of the fibrous cap is a promising strategy for preventing acute coronary syndrome and stroke, excessive fibrosis facilitates atherosclerotic lesions and limits artery blood flow. Thus, a better understanding of the mechanisms that regulate the ECM in atherosclerotic lesions is required.