MnTBAP attenuates pulmonary hypertension-induced right ventricular dysfunction and remodeling by modulating the CaMKIIδ-SERCA2a signaling pathway

A life-threatening condition, pulmonary arterial hypertension (PAH) is typified by the progressive pathological remodeling of pulmonary blood vessels, which progresses to right heart failure (RHF). The pathophysiological mechanisms underlying the progression from PAH to RHF remain unclear. Manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) is a synthetic manganese-based superoxide dismutase (SOD) mimetic with anti-inflammatory and antioxidant properties, attenuating PAH. This study investigated whether MnTBAP directly affects RHF in rats with monocrotaline (MCT)-induced PAH. Our data demonstrated that MnTBAP exerts pleiotropic beneficial effects in MCT-induced PAH rats: it inhibits the progression of PAH, prevents and reverses PAH-mediated right ventricular (RV) hypertrophy, fibrosis, and oxidative stress, and ultimately improves RV dysfunction. Its therapeutic effects are potentially achieved through suppressing aberrant CaMKIIδ phosphorylation in the myocardium of rats with PAH. Meanwhile, MnTBAP was found to downregulate abnormally activated Calcineurin A and sodium-calcium exchanger type 1 (NCX1), while restoring the phosphorylation level of phospholamban (PLN), thereby reconstructing the expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) and effectively alleviating MCT‑induced RHF. In conclusion, MnTBAP may exhibit potential therapeutic efficacy in treating PAH‑associated RHF, providing a scientific basis for further research into promising drug candidates for this condition.