Smooth muscle myosin heavy chains (MHCs) exist in multiple isoforms. Rabbit smooth muscles contain at least three types of MHC isoforms: SM1 (204 kD), SM2 (200 kD), and SMemb (200 kD). SM1 and SM2 are specific to smooth muscles, but SMemb is a nonmuscle-type MHC abundantly expressed in the embryonic aorta. We recently reported that these three MHC isoforms are differentially expressed in rabbit during normal vascular development and in experimental arteriosclerosis and atherosclerosis. The purpose of this study was to clarify whether expression of human smooth muscle MHC isoforms is regulated in developing arteries and in atherosclerotic lesions. To accomplish this, we have isolated and characterized three cDNA clones from human smooth muscle: SMHC94 (SM1), SMHC93 (SM2), and HSME6 (SMemb). The expression of SM2 mRNA in the fetal aorta was significantly lower as compared with SM1 mRNA, but the ratio of SM2 to SM1 mRNA was increased after birth. SMemb mRNA in the aorta was decreased after birth but appeared to be increased in the aged. To further examine the MHC expression at the histological level, we have developed three antibodies against human SMI, SM2, and SMemb using the isoform-specific sequences of the carboxyl terminal end. Immunohistologically, SMI was constitutively positive from the fetal stage to adulthood in the apparently normal media of the aorta and coronary arteries, whereas SM2 was negative in fetal arteries of the early gestational stage. In human, unlike rabbit, aorta or coronary arteries, SMemb was detected even in the adult. However, smaller-sized arteries, like the vasa vasorum of the aorta or intramyocardial coronary arterioles, were negative for SMemb. Diffuse intimal thickening in the major coronary arteries was found to be composed of smooth muscles, reacting equally to three antibodies for MHC isoforms, but reactivities with anti-SM2 antibody were reduced with aging. With progression of atherosclerosis, intimal smooth muscles diminished the expression of not only SM2 but also SM1, whereas cr-smooth muscle actin was well preserved. We conclude from these results that smooth muscle MHC isoforms are important molecular markers for studying human vascular smooth muscle cell differentiation as well as the cellular mechanisms of atherosclerosis. (Circ Res. 1993;73:1000-1012

Coronary artery disease (CAD) has become a major health problem in many countries. Recent genomewide association studies have identified the association between rs1333049 on chromosome 9p21 and susceptibility to CAD in Caucasoid populations. In this study, we evaluated the associations of rs1333049 with CAD in Japanese (604 patients and 1,151 controls) and Koreans (679 patients and 706 controls). We found a significant association in both Japanese [odds ratio (OR) = 1.30, 95% confidence interval (CI); 1.13-1.49, p = 0.00027, allele count model] and Koreans (OR = 1.19, 95% CI; 1.02-1.38, p = 0.025, allele count model). These observations demonstrated that chromosome 9p21 was the susceptibility locus for CAD also in East Asians.

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These studies suggest that the adventitia may play a role in vascular lesion formation after balloon overstretch injury of pig coronary arteries by contributing to the cellular mass of the neointima and the synthesis of growth factors. In addition, the adventitia may contribute to vascular remodeling and constriction of the external elastic lamina through accumulation of myofibroblasts containing alpha smooth muscle actin in the adventitia surrounding the injury site. Inhibition of myofibroblast proliferation and/or recruitment by intravascular brachytherapy positively affects vascular remodeling through its action on adventitial cells. Inflammation is a major event associated with balloon angioplasty, resulting in the sequential recruitment of neutrophils (2‐24 hours) and monocyte/macrophages (24‐72 hours) predominantly into the adventitia surrounding the injury site. It is hypothesized that inflammatory cells release cytokines and/or increase the production of superoxides which stimulate the proliferation and recruitment of adventitial myofibroblasts. Inflammatory and proliferative responses were not confined to the local adventitia but were found extending as far as 1‐3 mm away from the injured vessel in the distal perivascular tissues. Studies were performed to examine the expression of genes associated with cell migration at early times after injury in an attempt to determine the source of the adventitial myofibroblasts. Expression of genes involved in cell migration including MMP‐2, MMP‐9, and tenascin was found as early as 2 hours following angioplasty in the intramyocardial, pericardial, and adipose tissue fibroblasts. While these studies suggest that local tissue was the source of the myofibroblasts recruited to the injury site, we have been unable to confirm this finding by direct fluorescent labeling of adventitial cells. Recent work from our laboratory suggests that myofibroblast precursors may be isolated from buffy coat preparations from peripheral blood. These results lead us to hypothesize that stem cells that differentiate into myofibroblasts may be recruited in early inflammatory infiltrates in the adventitia. Clearly, additional work will have to be directed at a more detailed examination of the response of adventitial and other perivascular cells and tissues to balloon injury to determine their sources and their role in regulating vascular lesion development.