Abstract
During aging, and development of atherosclerosis and cardiovascular disease (CVD), aortic vascular smooth muscle cells (VSMCs) transition from healthy contractile to diseased synthetic phenotypes. K-Cl cotransport (KCC) maintains cell volume and ion homeostasis in growth and differentiation, and hence is important for VSMC proliferation and migration. Therefore, KCC activity may play a role in the contractile-to-synthetic VSMC phenotypic transition. Early, medium, and late synthetic passage VSMCs were tested for specific cytoskeletal protein expression. KCC-mediated ouabain- and bumetanide-insensitive Rb+ (a K+ congener) influx was determined as Cl--dependent Rb+ influx at different external Rb+ and Cl- ion concentrations, [Rb+]o and [Cl-]o. Expressions of the cytoskeletal proteins α-actin, vimentin, and desmin fell from early through late synthetic VSMCs. KCC kinetic parameters, such as maximum velocity ( Vm), and apparent Cl- and Rb+ affinities ( Km), were calculated with Lineweaver-Burk, Hanes-Woolf, and Hill approximations. Vm values of both Rb+- and Cl--dependent influxes were of equal magnitude, commensurate with a KCC stoichiometry of unity, and rose threefold from early to late synthetic VSMCs. Hill coefficients for Rb+ and Cl- correlated with cell passage number, suggesting increased KCC ligand cooperativity. However, Km values for [Cl-]o were strikingly bimodal with 60-80 mM in early, ~20-30 mM in medium, and 60 mM in late passage cells. In contrast, Km values for [Rb+]o remained steady at ~17 mM. Since total KCC isoform expression was similar with cell passage, structure/function changes of the KCC signalosome may accompany the transition of aortic VSMCs from a healthy to a diseased phenotype.
Highlights
Cardiovascular disease (CVD), including atherosclerosis, results in significant morbidity and mortality worldwide [55], and in the United States atherosclerosis accounts for more than 400,000 deaths annually [60, 68]
that may contribute to our understanding of the pathological progression
its tissue-specific isoforms may exert their participation through abnormalities or changes in their kinetic parameters
Summary
Cardiovascular disease (CVD), including atherosclerosis, results in significant morbidity and mortality worldwide [55], and in the United States atherosclerosis accounts for more than 400,000 deaths annually [60, 68]. CVD involves buildup of plaques in blood vessel walls restricting blood flow. Proliferation of vascular smooth muscle cells (VSMCs) and migration from the media to the intima augment enlargement and restructuring of the atherosclerotic lesion in the blood vessel wall [69, 85]. Narrowing of blood vessels caused by atherosclerosis is a chronic inflammatory response with recruitment of macrophages, lymphocytes, and platelets from circulating blood [67]. All these factors restrict blood flow and significantly increase the likelihood of a heart attack or stroke [57, 68]
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