TY - JOUR
T1 - The role of pulmonary vascular contractile protein expression in pulmonary arterial hypertension
AU - Konik, Ewa A.
AU - Han, Young Soo
AU - Brozovich, Frank V.
N1 - Funding Information:
We thank Dr Ozgur Ogut for his invaluable discussions, advice and comments on the manuscript. This study was supported by the Mayo Clinic .
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/12
Y1 - 2013/12
N2 - Pulmonary arterial hypertension (PAH) is associated with refractory vasoconstriction and impaired NO-mediated vasodilatation of the pulmonary vasculature. Vascular tone is regulated by light chain (LC) phosphorylation of both nonmuscle (NM) and smooth muscle (SM) myosins, which are determined by the activities of MLC kinase and MLC phosphatase. Further, NO mediated vasodilatation requires the expression of a leucine zipper positive (LZ. +) isoform of the myosin targeting subunit (MYPT1) of MLC phosphatase. The objective of this study was to define contractile protein expression in the pulmonary arterial vasculature and vascular reactivity in PAH. In severe PAH, compared to controls, relative LZ+MYPT1 expression was decreased (100. ±. 14% vs. 60. ±. 6%, p < 0.05, n = 7-8), and NM myosin expression was increased (15 ± 4% vs. 53. ± 5% of total myosin, p < 0.05, n = 4-6). These changes in contractile protein expression should alter vascular reactivity; following activation with Ang II, force activation and relaxation were slowed, and sustained force was increased. Further, the sensitivity to ACh-mediated relaxation was reduced. These results demonstrate that changes in the pulmonary arterial SM contractile protein expression may participate in the molecular mechanism producing both the resting vasoconstriction and the decreased sensitivity to NO-mediated vasodilatation associated with PAH.
AB - Pulmonary arterial hypertension (PAH) is associated with refractory vasoconstriction and impaired NO-mediated vasodilatation of the pulmonary vasculature. Vascular tone is regulated by light chain (LC) phosphorylation of both nonmuscle (NM) and smooth muscle (SM) myosins, which are determined by the activities of MLC kinase and MLC phosphatase. Further, NO mediated vasodilatation requires the expression of a leucine zipper positive (LZ. +) isoform of the myosin targeting subunit (MYPT1) of MLC phosphatase. The objective of this study was to define contractile protein expression in the pulmonary arterial vasculature and vascular reactivity in PAH. In severe PAH, compared to controls, relative LZ+MYPT1 expression was decreased (100. ±. 14% vs. 60. ±. 6%, p < 0.05, n = 7-8), and NM myosin expression was increased (15 ± 4% vs. 53. ± 5% of total myosin, p < 0.05, n = 4-6). These changes in contractile protein expression should alter vascular reactivity; following activation with Ang II, force activation and relaxation were slowed, and sustained force was increased. Further, the sensitivity to ACh-mediated relaxation was reduced. These results demonstrate that changes in the pulmonary arterial SM contractile protein expression may participate in the molecular mechanism producing both the resting vasoconstriction and the decreased sensitivity to NO-mediated vasodilatation associated with PAH.
KW - Myosin light chain phosphatase
KW - Myosin phosphatase targeting subunit 1
KW - Nitric oxide
KW - Nonmuscle myosin
KW - Smooth muscle myosin
KW - Vascular reactivity
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U2 - 10.1016/j.yjmcc.2013.10.009
DO - 10.1016/j.yjmcc.2013.10.009
M3 - Article
C2 - 24161910
AN - SCOPUS:84887196546
SN - 0022-2828
VL - 65
SP - 147
EP - 155
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -