title: The role of pulmonary vascular contractile protein expression in pulmonary arterial hypertension.
abstract: 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 (1 5 ± 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.
authors.affiliation: Mayo Clinic, Division of Cardiovascular Diseases, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Ewa A
authors.initials: EA
authors.lastname: Konik
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Han
authors.forename: Frank V
authors.initials: FV
authors.lastname: Brozovich
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003285:Contractile Proteins / Q000378:metabolism*; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology*; D066298:In Vitro Techniques; D016350:Leucine Zippers; D008168:Lung / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018995:Myosin Heavy Chains / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D003285:Contractile Proteins; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D018995:Myosin Heavy Chains; D000109:Acetylcholine
keywords: Myosin light chain phosphatase; Myosin phosphatase targeting subunit 1; Nitric oxide; Nonmuscle myosin; Smooth muscle myosin; Vascular reactivity