title: Smooth muscle-selective CPI-17 expression increases vascular smooth muscle contraction and blood pressure.
abstract: Recent data revealed that protein kinase C-potentiated myosin phosphatase inhibitor of 17 kDa (CPI-17), a myosin phosphatase inhibitory protein preferentially expressed in smooth muscle, is upregulated/activated in several diseases but whether this CPI-17 increase plays a causal role in pathologically enhanced vascular smooth muscle contractility and blood pressure remains unclear. To address this possibility, we generated a smooth muscle-specific CPI-17 transgenic mouse model (CPI-17-Tg) and demonstrated that the CPI-17 transgene was selectively expressed in smooth muscle-enriched tissues, including mesenteric arteries. The isometric contractions in the isolated second-order branch of mesenteric artery helical strips from CPI-17-Tg mice were significantly enhanced compared with controls in response to phenylephrine, U-46619, serotonin, ANG II, high potassium, and calcium. The perfusion pressure increases in isolated perfused mesenteric vascular beds in response to norepinephrine were also enhanced in CPI-17-Tg mice. The hypercontractility was associated with increased phosphorylation of CPI-17 and 20-kDa myosin light chain under basal and stimulated conditions. Surprisingly, the protein levels of rho kinase 2 and protein kinase Cα/δ were significantly increased in CPI-17-Tg mouse mesenteric arteries. Radiotelemetry measurements demonstrated that blood pressure was significantly increased in CPI-17-Tg mice. However, no vascular remodeling was detected by morphometric analysis. Taken together, our results demonstrate that increased CPI-17 expression in smooth muscle promotes vascular smooth muscle contractility and increases blood pressure, implicating a pathological significant role of CPI-17 upregulation.
authors.affiliation: Department of Physiology, University of Kentucky Medical Center, Lexington, KY, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.forename: Zhongwen
authors.initials: Z
authors.lastname: Xie
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Calderon
authors.forename: Zhenheng
authors.initials: Z
authors.lastname: Guo
authors.forename: Ming C
authors.initials: MC
authors.lastname: Gong
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007537:Isometric Contraction / Q000187:drug effects / Q000235:genetics*; D008638:Mesenteric Arteries / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D014158:Transcription, Genetic; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C491520:Ppp1r14a protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D012701:Serotonin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011188:Potassium; D002118:Calcium
keywords: hypercontractility; phosphatase inhibitory protein; protein kinase C-potentiated myosin phosphatase inhibitor of 17 kilodaltons