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K Ca 3.1 contributes to atherosclerotic lesion development induced by low, oscillatory flow
Author(s) -
Bowles Doug K,
Tharp Darla L
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.522.4
Subject(s) - lesion , artery , medicine , restenosis , vascular smooth muscle , apolipoprotein e , chemistry , endocrinology , pathology , smooth muscle , stent , disease
Increased expression of K Ca 3.1 has been found in vascular smooth muscle (VSM), macrophages and T cells in atherosclerotic lesions from humans and mice. Proliferating VSM cells increase expression of K Ca 3.1, such that it becomes a dominant K + channel and contributes to VSM cell migration. Previously, we showed that the K Ca 3.1 inhibitor, TRAM‐34, could inhibit coronary neointimal development following coronary balloon injury in swine. In the current study, we tested the role of K Ca 3.1 in atherosclerotic lesion development using two mouse models of atherosclerosis. First, partial carotid ligation (PCL), which produces a low, oscillatory (i.e. atheroprone) flow pattern in the left carotid artery was performed on 6–8 week old male Apoe −/− mice. Mice were subsequently placed on a Western diet (WD; TD.88137, Teklad) for 4 weeks and received daily s.c. injections of TRAM‐34 (120 mg/kg) or equal volumes of vehicle (peanut oil). To directly test the role of K Ca 3.1 we used CRISPR/Cas9 to generate K Ca 3.1 −/− Apoe −/− (DKO) mice. Subsequently, we examined lesion development in the brachiocephalic artery (BCA) of DKO vs. Apoe −/− male mice on a WD for 3 months. In PCL mice, TRAM‐34 treatment reduced lesion size ~50% (p<0.05). In addition, lesions from TRAM‐34 treated mice contained significantly less collagen (6 ± 1% v. 15 ± 2%; p<0.05), fibronectin (14±3% v. 32±3%; p<0.05) and smooth muscle content (19±2% v. 29±3%; p<0.05). Similarly, in BCAs of DKO mice, both lesion size (0.036 vs. 0.118 mm 2 , p<0.05) and relative stenosis (13.9% vs. 43.0%, p<0.05) were reduced 70% compared to Apoe −/− mice with no effect on medial or lumen area. Neither TRAM‐34 nor K Ca 3.1 silencing had any effect on total cholesterol or body weight. These data provide the first genetic validation defining a major role of K Ca 3.1 in lesion development and determining smooth muscle and matrix content of atherosclerotic lesions. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .