K Ca 3.1 inhibition decreases size and alters composition of atherosclerotic lesions induced by low, oscillatory flow

Abstract

Low, oscillatory flow/shear patterns are associated with atherosclerotic lesion development. Increased expression of KCa3.1 has been found in vascular smooth muscle (VSM), macrophages and T cells in lesions from humans and mice. Proliferating VSM increase expression of KCa3.1, such that it becomes a dominant K+ channel. KCa3.1 is also required for PDGF-induced VSM cell migration and we showed that the specific KCa3.1 inhibitor, TRAM-34, could inhibit coronary lesion development following balloon injury in swine. To determine the role of KCa3.1 in atherosclerotic lesion composition and development, we used the partial carotid ligation (PCL) model in high-fat fed, Apoe-/- mice which produces a low, oscillatory (i.e. atheroprone) flow pattern in the left carotid artery. PCL was performed on 6-8 week old male Apoe-/- mice. Mice were subsequently placed on a Western diet (TD.88137, Teklad) for 4 weeks and received daily s.c. injections of TRAM-34 (120 mg/kg; n=6) or equal volumes of vehicle (peanut oil, n=6). TRAM-34 treatment reduced lesion size 50% (p<0.05). In addition, lesions from TRAM-34 treated mice vs. controls contained significantly less collagen (6 ± 1% v. 15 ± 2%; p<0.05) and fibronectin (14±3% v. 32±3%; p<0.05). Consistent with the role of intimal smooth muscle in matrix-production, smooth muscle content of the lesions was also significantly reduced by TRAM-34 (19±2% v. 29±3%; p<0.05). Conversely, TRAM-34 had no effect on total cholesterol (1455 vs. 1334 mg/dl, PO and TRAM, resp.) or body weight (29.1 vs. 28.8 g, PO and TRAM, resp.). Together, these data support a major role for KCa3.1 in determining smooth muscle and matrix content of atherosclerotic lesions.