FIGURE 7.

Schematic illustration of the proposed mechanisms of tissue damage under conditions of PAH based on the main findings from this study. In PAH, pThr²³¹/Ser²³²‐RIP3 is increased in both RV and lung tissue. In the RVs, such elevation proceeds to the phosphorylation of MLKL, strongly indicating necroptotic cardiac damage, which is likely mediated by the accumulation of MLKL in the plasma membrane causing its rupture. On the contrary, elevated pThr²³¹/Ser²³²‐RIP3 in the lungs activates the NLRP3–csp‐1–GSDMD pathway, suggesting pyroptotic damage of the lungs, likely mediated by the creation of GSDMD pores in the plasma membrane resulting in its rupture and release of HMGB1. Furthermore, plasma levels of RIP3 are elevated in PAH and might serve as a potential diagnostic and prognostic biomarker for cardiac injury. (PAH—pulmonary arterial hypertension; RIP3—receptor‐interacting protein kinase 3; RV—right ventricle; MLKL—mixed lineage kinase domain‐like protein; NLRP3—NLR family pyrin domain containing 3; csp‐1—caspase‐1; GSDMD—gasdermin D; HMGB1—high mobility group box 1 protein)