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      Cardiotonic Steroids Induce Vascular Fibrosis Via Pressure-Independent Mechanism in NaCl-Loaded Diabetic Rats

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          Abstract

          Endogenous cardiotonic steroid, marinobufagenin (MBG), induces Fli1-dependent tissue fibrosis. We hypothesized that an increase in MBG initiates the development of aortic fibrosis in salt-loaded rats with type 2 diabetes mellitus (DM2) via pressure-independent mechanism. DM2 was induced by a single intraperitoneal administration of 65 mg/kg streptozotocin to neonatal (4–5 days) male Wistar rats. Eight-week-old DM2 rats received water or 1.8% NaCl (DM-NaCl) solution for 4 weeks (n = 16); half of DM-NaCl rats were treated with anti-MBG monoclonal antibody (mAb) (DM-NaCl-AB) during week 4 of salt loading; control intact rats received water (n = 8/group). Blood pressure, MBG, erythrocyte Na/K-ATPase activity, aortic weights, levels of fibrosis markers (Fli1, protein kinase Cδ, transforming growth factor-β1, receptors of the transforming growth factor beta5, fibronectin, collagen-1), and sensitivity of the aortic explants to the vasorelaxant effect of sodium nitroprusside were assessed. No changes in systolic blood pressure were observed while erythrocyte Na/K-ATPase was inhibited by 30%, plasma MBG was doubled, and aortic markers of fibrosis became elevated in DM-NaCl rats versus control. Treatment of DM-NaCl rats with anti-MBG mAb activated Na/K-ATPase, prevented increases in aortic weights, and the levels of fibrosis markers returned to the control levels. The responsiveness of the aortic rings from DM-NaCl rats to the relaxant effect of sodium nitroprusside was reduced (half maximal effective concentration (EC 50) = 29 nmol/L) versus control rings (EC 50 = 7 nmol/L) and was restored by anti-MBG mAb (EC 50 = 9 nmol/L). Our results suggest that in salt-loaded diabetic rats, MBG stimulates aortic collagen synthesis in a pressure-independent fashion and that 2 profibrotic mechanisms, Fli1 dependent and transforming growth factor-β dependent, underlie its effects.

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          Author and article information

          Journal
          7902492
          5285
          J Cardiovasc Pharmacol
          J. Cardiovasc. Pharmacol.
          Journal of cardiovascular pharmacology
          0160-2446
          1533-4023
          3 September 2020
          November 2019
          23 September 2020
          : 74
          : 5
          : 436-442
          Affiliations
          [* ]National Institute on Aging, NIH, Baltimore, MD;
          []Almazov National Medical Research Centre, St. Petersburg, Russia. Fadeev is now with Laboratory of Molecular Virology, Research Institute of Influenza, St. Petersburg, Russia;
          []Institute of Highly Pure Biopreparations, St. Petersburg, Russia;
          [§ ]Sechenov Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia.
          Author notes
          Reprints: Alexei Y. Bagrov, PhD, MD, Sechenov Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia 194223 ( aybagrov@ 123456gmail.com ).
          Article
          PMC7508669 PMC7508669 7508669 nihpa1625257
          10.1097/FJC.0000000000000730
          7508669
          31415452
          3fc39424-2d62-4c8b-9dc0-21c60da5f7c9
          History
          Categories
          Article

          aorta,inhibitors,vascular stiffness,diabetes mellitus,sodium chloride,Na/K-ATPase,marinobufagenin,TGF-β,cellular signaling,streptozotocin,Fli1

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