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Protein Changes Contributing to Right Ventricular Cardiomyocyte Diastolic Dysfunction in Pulmonary Arterial Hypertension | Journal Scan
Study Questions:
Right ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Which, if any, protein modifications contribute to cellular diastolic dysfunction in PAH?
Methods:
RV samples from PAH patients undergoing heart-lung transplantation were compared to nonfailing donors (Don). Titin stiffness contribution to RV diastolic dysfunction was determined by Western-blot analyses using antibodies to proteinkinase-A (PKA), Cα (PKCα) and Ca2+/calmoduling-dependent-kinase (CamKIIδ) titin and phospholamban (PLN) phosphorylation sites: N2B (Ser469), PEVK (Ser170 and Ser26), and PLN (Thr17), respectively. PKA and PKCα sites were significantly less phosphorylated in PAH compared with donors (p < 0.0001). To test the functional relevance of PKA-, PKCα-, and CamKIIδ-mediated titin phosphorylation, the authors measured the stiffness of single RV cardiomyocytes before and after kinase incubation.
Results:
PKA significantly decreased PAH RV cardiomyocyte diastolic stiffness, PKCα further increased stiffness, while CamKIIδ had no major effect. CamKIIδ activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca2+ sensitivity is mediated by sarcomeric troponin I (cTnI) phosphorylation. The authors observed increased unphosphorylated cTnI in PAH compared with donors (p < 0.05) and reduced PKA-mediated cTnI phosphorylation (Ser22/23) (p < 0.001). Finally, alterations in Ca2+-handling proteins contribute to RV diastolic dysfunction due to insufficient diastolic Ca2+ clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (p < 0.05).
Conclusions:
The authors concluded that increased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca2+ handling proteins contribute to RV diastolic dysfunction in PAH.
Perspective:
The authors previously reported that elevated cardiomyocyte stiffness and myofilament Ca2+ sensitivity underlie diastolic dysfunction in PAH. Right heart failure with preserved ejection fraction (HFpEF) (similar to left HFpEF) is an important unrecognized and poorly understood clinical syndrome, but this study, conducted in PAH patients with severe RV systolic failure undergoing heart-lung transplant, does not address that cohort. Nevertheless, the molecular protein findings in this study differ from those found in LV HFpEF and offer the potential for new targets to reduce RV filling and RA pressure, and the consequences of high venous pressures on the liver and periphery.
Keywords: Calcium-Binding Proteins, Connectin, Cyclic AMP-Dependent Protein Kinases, Heart Failure, Heart-Lung Transplantation, Phosphorylation, Hypertension, Pulmonary, Myocytes, Cardiac, Myofibrils, Troponin I, Ventricular Function, Right
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