Pediatr Res. 2017 Apr;81(4):593-600. doi: 10.1038/pr.2016.266. Epub 2016 Dec 20.

Losartan attenuates the coronary perivasculitis through its local and systemic anti-inflammatory properties in a murine model of Kawasaki disease.

Suganuma E1,2, Niimura F1, Matsuda S1, Ukawa T1, Nakamura H1, Sekine K1, Kato M1, Aiba Y3, Koga Y3, Hayashi K4, Takahashi O4, Mochizuki H1.

1Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan.
2Division of Infectious Diseases and Immunology, Saitama Children’s Medical Center, Saitama, Japan.
3Laboratory for Infectious Disease, Tokai University School of Medicine, Kanagawa, Japan.
4Laboratory Center for Clinical Epidemiology, St. Luke’s International University, Tokyo, Japan.

Abstract

BACKGROUND:

Kawasaki disease is a common systemic vasculitis that leads to coronary artery lesions. Besides its antihypertensive effects, losartan can modulate inflammation in cardiovascular disease. We examined whether losartan can attenuate coronary inflammation in a murine model of Kawasaki disease.

METHODS AND RESULTS:

Five-wk-old C57/BL6J male mice were intraperitoneally injected with Lactobacillus casei cell wall extract to induce coronary inflammation and divided into four groups: placebo, intravenous immunoglobulin (IVIG), losartan, and IVIG+losartan. After 2 wk, mice were harvested. The coronary perivasculitis was significantly attenuated by losartan but not by IVIG alone, and further dramatic attenuation by IVIG+losartan was observed. The frequency of Lactobacillus casei cell wall extract-induced myocarditis (80%) was markedly lowered by losartan (22%) and IVIG+losartan (0%). Furthermore, interleukin (IL)-6 mRNA was markedly attenuated by IVIG+losartan. Serum levels of IL-6, TNF-α, MCP-1, and IL-10 after Lactobacillus casei cell wall extract injection were slightly decreased by IVIG or losartan. Moreover, IL-1β, IL-10, and MCP-1 levels were significantly decreased by IVIG+losartan.

CONCLUSION:

The addition of losartan to IVIG strongly attenuated the severity of coronary perivasculitis and the incidence of myocarditis, along with suppressing systemic/local cytokines as well as the activated macrophage infiltration. Therefore, losartan may be a potentially useful additive drug for the acute phase of Kawasaki disease to minimize coronary artery lesions.

PMID: 27997528

 

Supplement

Kawasaki disease (KD) is an acute systemic vasculitis that mostly affects in children, and not infrequently involves the coronary arteries, resulting in cardiovascular sequelae such as coronary artery lesions (CALs) [1]. Although many additional treatments are currently available, CALs develop in some patients and are still an important problem in the treatment of KD in children.

 Besides their antihypertensive effects, angiotensin receptor blockers (ARBs) are also known to suppress cell infiltration in some cardiovascular diseases, including atherosclerosis [2]. Lactobacillus casei cell wall extract (LCWE)-induced coronary arteritis/perivasculitis is a well-established murine model of KD [3]. Therefore, in this study, we chose to use the murine model of LCWE-induced coronary arteritis/perivasculitis.

Furthermore, there are some pathological common features between KD-related vasculitis and atherosclerosis, including the destruction of the vascular architecture, although the time course and susceptible age are quite different. Thus, it is reasonable to speculate that ARB has some beneficial effects in KD-related coronary involvement as well as in atherosclerosis and aneurysms. In this paper, we concluded that the addition of losartan to IVIG treatment dramatically attenuated coronary perivasculitis and myocarditis in a murine model of KD. Losartan exerts its effects through suppressing systemic cytokines and chemokines, and also through suppressing the local macrophage infiltration and IL-6 mRNA expression. Therefore, losartan may be a potentially useful additive drug for the acute phase of KD aiming at preventing CALs.

 

Acknowledgements:

This study was supported in part by JSPS KAKENHI grant no. 20790750, Grant-in-Aid for Young Scientists (B).

 

Contact:

Eisuke Suganuma, MD, PhD

Division of Infectious Diseases and Immunology, Saitama Children’s Medical Center, Saitama 330-8777, Japan

E-mail: suganuma.eisuke@scmc.pref.saitama.jp

 

Reference:

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