Urotensin II induces activation of NLRP3 and pyroptosis through calcineurin in cardiomyocytes.

Abstract Cell pyroptosis, a new type of programmed cell death, has been recently reported to play important roles in the development of cardiac remodeling. How cardiomyocyte pyroptosis is induced remains to be elucidated. Urotensin II (UII) has been known closely related to cardiac remodeling and the development of heart failure. Inhibition of UII receptors has been shown to be effective in the treatment of cardiac hypertrophy and remodeling. However, it is not clear whether UII might induce cardiomyocyte pyroptosis. We here examined the effect of UII treatment on pyroptosis in cultured cardiomyocytes. Treatment of cardiomyocyes of neonatal rats with UII (500 nmol/l) for 48 hours induced a significant pyroptosis as evidenced by not only increased cell death but also upregulated expression levels of NLR family pyrin domain containing 3 (NLRP3), caspase-1, IL-1β, IL-18 and gasdermin D (GMDSD)-N which are important markers for the identification of cell pyroptosis. All these pyroptosis responses induced by UII were abrogated by an inhibitor of NLRP3. Moreover, the antagonist of UII receptor, Urantide abolished UII- induced cardiomyocyte pyroptosis. Additionally, inhibition of calcineurin by cyclosporin A rather than that of CaMKII by KN93 suppressed the UII-upregulated expression levels of those pyroptosis markers. We therefore demonstrate that UII might induce cardiomyocyte pyroptosis through calcineurin.