title: Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension.
abstract: Increased aortic stiffness is a fundamental manifestation of hypertension. However, the molecular mechanisms involved remain largely unknown. We tested the hypothesis that abnormal intrinsic vascular smooth muscle cell (VSMC) mechanical properties in large arteries, but not in distal arteries, contribute to the pathogenesis of aortic stiffening in hypertension, mediated by the serum response factor (SRF)/myocardin signalling pathway.
  
  
  
  Four month old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Using atomic force microscopy, significant VSMC stiffening was observed in the large conducting aorta compared with the distal arteries in SHR (P < 0.001), however, this regional variation was not observed in WKY rats (P > 0.4). The increase of VSMC stiffness was accompanied by a parallel increase in the expression of SRF by 9.8-fold and of myocardin by 10.5-fold in thoracic aortic VSMCs from SHR vs. WKY rats, resulting in a significant increase of downstream stiffness-associated genes (all, P < 0.01 vs. WKY). Inhibition of SRF/myocardin expression selectively attenuated aortic VSMC stiffening, and normalized downstream targets in VSMCs isolated from SHR but not from WKY rats. In vivo, 2 weeks of treatment with SRF/myocardin inhibitor delivered by subcutaneous osmotic minipump significantly reduced aortic stiffness and then blood pressure in SHR but not in WKY rats, although concomitant changes in aortic wall remodelling were not detected during this time frame.
  
  
  
  SRF/myocardin pathway acts as a pivotal mediator of aortic VSMC mechanical properties and plays a central role in the pathological aortic stiffening in hypertension. Attenuation of aortic VSMC stiffening by pharmacological inhibition of SRF/myocardin signalling presents a novel therapeutic strategy for the treatment of hypertension by targeting the cellular contributors to aortic stiffness.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.|Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, 11041 Campus Street, Loma Linda, 92350 CA, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Department of Medicine (Cardiology), Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029 NY, USA; and.
authors.forename: Jia-Jye
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, 11041 Campus Street, Loma Linda, 92350 CA, USA.
authors.forename: Shaunrick
authors.initials: S
authors.lastname: Stoll
authors.affiliation: Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, 11041 Campus Street, Loma Linda, 92350 CA, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Medicine (Cardiology), Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029 NY, USA; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Wiener
authors.affiliation: Department of Basic Sciences/School of Medicine, Center for Genomics, Loma Linda University, 11021 Campus St., Loma Linda, 92350 CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medicine (Cardiology), Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029 NY, USA; and hqiu@llu.edu kevin.costa@mssm.edu.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Costa
authors.affiliation: Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, 11041 Campus Street, Loma Linda, 92350 CA, USA; hqiu@llu.edu kevin.costa@mssm.edu.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Qiu
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001013:Aorta, Thoracic / Q000378:metabolism / Q000503:physiopathology; D062186:Arterial Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D055104:Infusions, Subcutaneous; D008297:Male; D018625:Microscopy, Atomic Force; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009557:Nipecotic Acids / Q000008:administration & dosage*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059289:Vascular Stiffness / Q000187:drug effects*; D000099251:Myocardin
chemical_list: D000959:Antihypertensive Agents; D009557:Nipecotic Acids; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099251:Myocardin; C000623208:CCG-100602; C000620714:serum response factor, rat
keywords: Atomic force microscopy; Hypertension; Myocardin; Serum response factor; Vascular smooth muscle cell stiffness