Necroptosis and pyroptosis may mediate cellular damage within the right ventricle and lungs induced by pulmonary arterial hypertension (PAH), according to findings of a new study published in the Journal of Cellular and Molecular Medicine.
Researchers induced PAH in male Wistar rats with monocrotaline and divided them into 2 groups based on the severity of disease progression. The more severe disease manifestation resulted in a rapid decline in vital functions, requiring the premature sacrifice of these rats on day 24. The other group did not deteriorate as quickly, lasting a full 4 weeks prior to their termination.
The investigators performed a detailed immunoblotting analysis of the cardiac and pulmonary tissues to detect the presence of specific proteins associated with necroptosis and pyroptosis.
They determined that necroptosis caused right ventricular damage as demonstrated by the increased presence of the protein complexes, pThr231/Ser232-RIP3, and pSer345-MLKL. Activation of the receptor-interacting protein kinase 3 (RIP3)-containing complex results in the translocation of the mixed lineage kinase domain-like protein (MLKL) to the cell membrane where it provokes the cell membrane’s rupture and leads to cellular death via necroptosis, and that right ventricular heart failure is the leading cause of mortality in patients with PAH.
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In contrast, pyroptosis contributed to lung tissue damage as evidenced by the increased phosphorylation of pulmonary pThr231/Ser232-RIP3 which inhibited activation of MLKL, instead of leading to gasdermin D-mediated pyroptosis.
The investigators observed higher concentrations of plasma RIP3 in the group with more severe disease progression and a positive association with right ventricular hypertrophy as measured by the Fulton index. However, plasma RIP3 did not correlate with vital functions or specific markers of hemodynamic stress. This finding indicates that clinicians could use plasma RIP3 levels as a biomarker to diagnose and predict cardiac injury in patients with PAH.
“Taken together, these findings suggest the important and complex role of RIP3 in the pathogenesis of PAH and thus pharmacological targeting of this kinase might be a promising way to prevent cell death in PAH-induced injury of various tissues with resultant reduction of mortality,” the authors concluded.
Jarabicová I, Horváth C, Veľasová E, et al. Analysis of necroptosis and its association with pyroptosis in organ damage in experimental pulmonary arterial hypertension. J Cell Mol Med. Published online April 7, 2022. doi:10.1111/jcmm.17272