RATIONALE: RV adaptation in pulmonary hypertension is sexually dimorphic and more preserved in women. NLRP3 inflammasome activation contributes to RV failure (RVF) development. However, regulators and downstream effects of NLRP3 activation in the RV remain unknown. OBJECTIVES: We investigated whether NLRP3 inflammasome activation in RVF is sexually dimorphic, whether NLRP3 is active in RV cardiomyocytes (RVCMs) and causes RVCM contractile dysfunction, and whether 17beta-estradiol (E2) and its receptor ERalpha attenuate this process. METHODS: We studied RV tissues from PAH patients with RVF, RV tissues and RVCMs isolated from wild-type and ERalpha loss-of-function mutant rats with RVF, isolated perfused rat hearts, and human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. NLRP3 activation was assessed via RNA-sequencing, proteomics, immunostaining, and downstream target quantification. RV contractility was assessed via pressure-volume loops, perfused heart studies, and contractility and calcium assessments in isolated RVCMs. MEASUREMENTS AND MAIN RESULTS: NLRP3 was upregulated in RVCMs during RVF and resulted in altered RVCM calcium handling and RVCM contractile dysfunction. In human RVs, hiPSC-cardiomyocytes and rat RVs, NLRP3 activation and NLRP3-induced RVCM contractile dysfunction were sexually dimorphic and male-biased. Ovariectomy and loss of ERalpha in females eliminated this sex bias. E2, via ERalpha, prevented RVCM NLRP3 activation and NLRP3-induced RVCM contractile dysfunction in males and ovariectomized females during both acute and chronic RV pressure overload. ERalpha directly interacted with NLRP3. CONCLUSIONS: NLRP3-driven RVCM contractile dysfunction is male-biased. E2 inhibits NLRP3 through ERalpha to preserve RVCM contractility. Targeting E2-ERalpha-NLRP3 signaling may offer novel therapeutic strategies for RVF in low estrogen states. IMPACT: This is the first study to define a novel estradiol-estrogen receptor alpha-NLRP3 axis that modulates RV cardiomyocyte function and RV adaptation in pulmonary hypertension. We demonstrate for the first time that NLRP3 activation is therapeutically targetable in low estrogen states via NLRP3 inhibitors or 17beta-estradiol. These findings have direct implications for therapeutic strategies aimed at preserving or restoring RV contractile function in pulmonary hypertension, a current area of unmet clinical need.
- Fais, R. S.
- Palotta, E. D. N.
- Kopf, K. W.
- Massad, K. M.
- Neto-Neves, E. M.
- Hoffer, C.
- Walts, A. D.
- Frump, A. L.
- Goldenberg, N. M.
- Givens, S.
- Bourgeois, A.
- Woodcock, C. C.
- Petrache, I.
- Chesler, N. C.
- Woulfe, K. C.
- Pullamsetti, S. S.
- Boucherat, O.
- Provencher, S.
- Ogle, B. M.
- Bonnet, S.
- Lahm, T.
