Losartan Ameliorates Coronary Neointimal Thickening in a Mouse Model of Kawasaki Disease: A Pilot Study

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. In this exploratory study, the therapeutic effect of the angiotensin receptor blocker (ARB) losartan on coronary artery (CA) stenosis was investigated in a murine model. Methods: Five-week-old male C57BL/6J mice were intraperitoneally injected with 1000 μg of Lactobacillus casei cell wall extract (LCWE) (n = 12) to induce CA stenosis. Two weeks later, the 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 CA 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 (median [IQR (interquartile range)]: 0 [0–9.5] vs. 21.5 [15–24.3], p = 0.003). LCWE-induced neointimal formation with vascular smooth muscle cell proliferation and subsequent CA stenosis were markedly attenuated in losartan-treated mice (25% vs. 100%, p < 0.001). Losartan-associated attenuation of CA stenosis was accompanied by the preservation of medial calponin expression, a reduction in the number of proliferating cell nuclear antigen (PCNA)-positive cells in the neointima, and a decrease in serum MMP-9 (matrix metalloproteinase-9) levels. Conclusions: These findings from a murine model of KD provide preliminary evidence that losartan may attenuate coronary artery remodeling. Further mechanistic studies are warranted to clarify its potential translational relevance.