Open AccessLoss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload
Author(s) -
Prasad Vidhya,
Makkaoui Nour,
Rajan Rohan,
Patel Alisha,
Mainali Bipul,
Bagchi Pritha,
Kumar Rhea,
Rogers Julia,
Diamond Jake,
Maxwell Joshua T.
Publication year - 2022
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.15238
Subject(s) - pressure overload , contractility , medicine , ventricle , cardiology , muscle hypertrophy , myocyte , volume overload , heart failure , ventricular pressure , pulmonary artery banding , myosin light chain kinase , right ventricular hypertrophy , contraction (grammar) , myosin , pulmonary artery , hemodynamics , biology , cardiac hypertrophy , microbiology and biotechnology
Nearly 1 in every 100 children born have a congenital heart defect. Many of these defects primarily affect the right heart causing pressure overload of the right ventricle (RV). The RV maintains function by adapting to the increased pressure; however, many of these adaptations eventually lead to RV hypertrophy and failure. In this study, we aim to identify the cellular and molecular mechanisms of these adaptions. We utilized a surgical animal model of pulmonary artery banding (PAB) in juvenile rats that has been shown to accurately recapitulate the physiology of right ventricular pressure overload in young hearts. Using this model, we examined changes in cardiac myocyte protein expression as a result of pressure overload with mass spectrometry 4 weeks post‐banding. We found pressure overload of the RV induced significant downregulation of cardiac myosin light chain kinase (cMLCK). Single myocyte calcium and contractility recordings showed impaired contraction and relaxation in PAB RV myocytes, consistent with the loss of cMLCK. In the PAB myocytes, calcium transients were of smaller amplitude and decayed at a slower rate compared to controls. We also identified miR‐200c, which has been shown to regulate cMLCK expression, as upregulated in the RV in response to pressure overload. These results indicate the loss of cMLCK is a critical maladaptation of the RV to pressure overload and represents a novel target for therapeutic approaches to treat RV hypertrophy and failure associated with congenital heart defects.