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Losartan Ameliorates Coronary Neointimal Thickening in a Mouse Model of Kawasaki Disease: A Pilot Study
Eisuke Suganuma1, Satoko Honda2, Rina Umiguchi2
1Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, 2-1 Shintoshin Chuou-ku, Saitama 330-8777, Japan.
Insights
Losartan, an angiotensin receptor blocker, may help prevent coronary artery stenosis in a mouse model of Kawasaki disease. This study suggests losartan could reduce inflammation and remodeling in coronary arteries, offering potential therapeutic benefits.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Immunology
Background:
- Kawasaki disease (KD) patients with coronary artery aneurysms (CAAs) face high risks of fatal coronary events.
- Current pharmacotherapies to prevent coronary stenosis in KD are insufficient.
- This study explores losartan's effect on coronary artery stenosis in a murine model.
Purpose of the Study:
- To investigate the therapeutic effect of losartan, an angiotensin receptor blocker (ARB), on coronary artery (CA) stenosis.
- To evaluate losartan's impact on inflammation, neointimal formation, and vascular remodeling in a mouse model of Kawasaki disease.
Main Methods:
- Induction of coronary artery stenosis in mice using Lactobacillus casei cell wall extract (LCWE).
- Treatment of LCWE-injected mice with losartan or normal drinking water.
- Histological evaluation of coronary arteries and measurement of serum MMP-9 levels.
Main Results:
- Losartan significantly reduced the coronary arteritis score compared to untreated mice.
- LCWE-induced neointimal formation and CA stenosis were markedly attenuated by losartan.
- Losartan treatment preserved medial calponin expression, reduced PCNA-positive cells, and decreased serum MMP-9.
Conclusions:
- Losartan demonstrated preliminary efficacy in attenuating coronary artery remodeling in a murine model of Kawasaki disease.
- These findings suggest losartan may hold translational relevance for preventing coronary stenosis in KD patients.
- Further mechanistic studies are needed to fully elucidate losartan's therapeutic potential.
Abstract:
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.
