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

Olga V. Fedorova, Artem V. Fadeev, Yulia N. Grigorova, Courtney A. Marshall, Valentina Zernetkina, Nikolai I. Kolodkin, Natalia I. Agalakova, Alexandra O. Konradi, Edward G. Lakatta, Alexei Y. Bagrov

Research output: Contribution to journalArticlepeer-review

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 (EC50) = 29 nmol/L) versus control rings (EC50 = 7 nmol/L) and was restored by anti-MBG mAb (EC50 = 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.

Original languageEnglish (US)
Pages (from-to)436-442
Number of pages7
JournalJournal of cardiovascular pharmacology
Volume74
Issue number5
DOIs
StatePublished - Nov 1 2019

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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