Losartan Ameliorates Coronary Neointimal Thickening via Vascular Smooth Muscle Cell Phenotype Modulation in a Mouse Model of Kawasaki Disease

Background: Patients with Kawasaki disease (KD) who develop coronary artery aneurysms (CAAs) are at increased risk of future fatal coronary events. Pharmacotherapeutic strategies to prevent coronary stenosis are still lacking. This study investigated the therapeutic effect of the angiotensin receptor blocker (ARB) losartan, on coronary artery stenosis in a murine model. Methods: Five-week-old male C57BL/6J mice were intraperitoneally injected with 1,000 μg of Lactobacillus casei cell wall extract (LCWE) (n=12) to induce coronary artery stenosis. Two weeks later, LCWE-injected mice (n=12) were divided into two groups: six received drinking water containing losartan (100 mg/L) (LCWE+ARB), while six received normal drinking water (LCWE group). A control group (n=5) received phosphate-buffered saline (PBS) instead of LCWE. Sixteen weeks after LCWE administration—corresponding to the peak of coronary artery stenosis and 14 weeks after treatment initiation—the mice were euthanized for histological evaluation of the coronary arteries. Results: Losartan treatment significantly reduced the coronary arteritis score (4.3±3.3 vs. 19.3±2.8, p=0.003). LCWE-induced neointimal formation with vascular smooth muscle cell (VSMC) proliferation and subsequent coronary artery stenosis were markedly attenuated in losartan-treated mice (25% vs. 100%, p<0.001). Moreover, losartan inhibited coronary artery stenosis, at least in part, by preventing the phenotypic switch of vascular VSMCs from a contractile to a synthetic phenotype. Conclusions: Losartan is a potential therapeutic agent for preventing coronary events in KD by suppressing intimal proliferation and modulating the VSMC phenotype.