Mechanistic Target of Rapamycin Inhibition Prevents Coronary Artery Remodeling in a Murine Model of Kawasaki Disease.

OBJECTIVE

Remodeling of the coronary arteries is a common feature in severe cases of Kawasaki disease (KD). This pathology is driven by the dysregulated proliferation of vascular fibroblasts, which can lead to coronary artery aneurysms, stenosis, and myocardial ischemia. We undertook this study to investigate whether inhibiting fibroblast proliferation might be an effective therapeutic strategy to prevent coronary artery remodeling in KD.

METHOD

We used a murine model of KD (induced by the injection of the Candida albicans water-soluble complex [CAWS]) and analyzed patient samples to evaluate potential antifibrotic therapies for KD.

RESULTS

We identified the mechanistic target of rapamycin (mTOR) pathway as a potential therapeutic target in KD. The mTOR inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, and vascular fibroblasts up-regulated mTOR kinase signaling in vivo in the CAWS mouse model of KD. We evaluated the in vivo efficacy of mTOR inhibition and found that the therapeutic administration of rapamycin reduced vascular fibrosis and intimal hyperplasia of the coronary arteries in CAWS-injected mice. Furthermore, the analysis of cardiac tissue from KD fatalities revealed that vascular fibroblasts localizing with inflamed coronary arteries up-regulate mTOR signaling, confirming that the mTOR pathway is active in human KD.

CONCLUSION

Our findings demonstrate that mTOR signaling contributes to coronary artery remodeling in KD, and that targeting this pathway offers a potential therapeutic strategy to prevent or restrict this pathology in high-risk KD patients.