Inhibition of apoptosis signal-regulating kinase 1 ameliorates left ventricular dysfunction by reducing hypertrophy and fibrosis in a rat model of cardiorenal syndrome.

Autor: Savira F; Biomarker Discovery Laboratory, Baker Heart and Diabetes Research Institute, Melbourne, Australia; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia., Wang BH; Biomarker Discovery Laboratory, Baker Heart and Diabetes Research Institute, Melbourne, Australia; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. Electronic address: bing.wang@baker.edu.au., Edgley AJ; Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia., Jucker BM; Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA, USA., Willette RN; Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA, USA., Krum H; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia., Kelly DJ; Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia., Kompa AR; Biomarker Discovery Laboratory, Baker Heart and Diabetes Research Institute, Melbourne, Australia; Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia. Electronic address: andrew.kompa@unimelb.edu.
Jazyk: angličtina
Zdroj: International journal of cardiology [Int J Cardiol] 2020 Jul 01; Vol. 310, pp. 128-136. Date of Electronic Publication: 2020 Apr 06.
DOI: 10.1016/j.ijcard.2020.04.015
Abstrakt: Background: Cardiorenal syndrome (CRS) is a major health burden worldwide in need of novel therapies, as current treatments remain suboptimal. The present study assessed the therapeutic potential of apoptosis signal-regulating kinase 1 (ASK1) inhibition in a rat model of CRS.
Methods: Adult male Sprague-Dawley rats underwent surgery for myocardial infarction (MI) (week 0) followed by 5/6 subtotal nephrectomy (STNx) at week 4 to induce to induce a combined model of heart and kidney dysfunction. At week 6, MI + STNx animals were randomized to receive either 0.5% carboxymethyl cellulose (Vehicle, n = 15, Sham = 10) or G226 (15 mg/kg daily, n = 11). Cardiac and renal function was assessed by echocardiography and glomerular filtration rate (GFR) respectively, prior to treatment at week 6 and endpoint (week 14). Haemodynamic measurements were determined at endpoint prior to tissue analysis.
Results: G226 treatment attenuated the absolute change in left ventricular (LV) fractional shortening and posterior wall thickness compared to Vehicle. G226 also attenuated the reduction in preload recruitable stroke work. Increased myocyte cross sectional area, cardiac interstitial fibrosis, immunoreactivity of cardiac collagen-I and III and cardiac TIMP-2 activation, were significantly reduced following G226 treatment. Although we did not observe improvement in GFR, G226 significantly reduced renal interstitial fibrosis, diminished renal collagen-I and -IV, kidney injury molecule-1 immunoreactivity as well as macrophage infiltration and SMAD2 phosphorylation.
Conclusion: Inhibition of ASK1 ameliorated LV dysfunction and diminished cardiac hypertrophy and cardiorenal fibrosis in a rat model of CRS. This suggests that ASK1 is a critical pathway with therapeutic potential in the CRS setting.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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