Cardioprotection by the adiponectin receptor agonist ALY688 in a preclinical mouse model of heart failure with reduced ejection fraction (HFrEF)

Sungji Cho; Keith Dadson; Hye Kyoung Sung; Oyeronke Ayansola; Ali Mirzaesmaeili; Nina Noskovicova; Yimu Zhao; Krisco Cheung; Milica Radisic; Boris Hinz; Ali A. Abdul Sater; Henry H. Hsu; Gary D. Lopaschuk; Gary Sweeney

Biomedicine & Pharmacotherapy (Feb 2024)

Cardioprotection by the adiponectin receptor agonist ALY688 in a preclinical mouse model of heart failure with reduced ejection fraction (HFrEF)

Sungji Cho,
Keith Dadson,
Hye Kyoung Sung,
Oyeronke Ayansola,
Ali Mirzaesmaeili,
Nina Noskovicova,
Yimu Zhao,
Krisco Cheung,
Milica Radisic,
Boris Hinz,
Ali A. Abdul Sater,
Henry H. Hsu,
Gary D. Lopaschuk,
Gary Sweeney

Affiliations

Sungji Cho: Department of Biology, York University, Toronto, ON, Canada
Keith Dadson: Department of Biology, York University, Toronto, ON, Canada
Hye Kyoung Sung: Department of Biology, York University, Toronto, ON, Canada
Oyeronke Ayansola: Department of Biology, York University, Toronto, ON, Canada
Ali Mirzaesmaeili: School of Kinesiology and Health Science, York University, Toronto, ON, Canada
Nina Noskovicova: Faculty of Dentistry, University of Toronto, Toronto, ON M5S3E2, Canada
Yimu Zhao: Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
Krisco Cheung: Department of Chemical Engineering and Applied Chemistry; University of Toronto, Toronto, ON M5S 3E5, Canada
Milica Radisic: Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Department of Chemical Engineering and Applied Chemistry; University of Toronto, Toronto, ON M5S 3E5, Canada
Boris Hinz: Faculty of Dentistry, University of Toronto, Toronto, ON M5S3E2, Canada; Laboratory of Tissue Repair and Regeneration, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1T8, Canada
Ali A. Abdul Sater: School of Kinesiology and Health Science, York University, Toronto, ON, Canada
Henry H. Hsu: Allysta Pharmaceuticals Inc. Bellevue, WA, USA
Gary D. Lopaschuk: Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
Gary Sweeney: Department of Biology, York University, Toronto, ON, Canada; Correspondence to: Department of Biology, York University, Toronto, M3J 1P3 ON, Canada.

Journal volume & issue: Vol. 171
p. 116119

Abstract

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Aims: Adiponectin has been shown to mediate cardioprotective effects and levels are typically reduced in patients with cardiometabolic disease. Hence, there has been intense interest in developing adiponectin-based therapeutics. The aim of this translational research study was to examine the functional significance of targeting adiponectin signaling with the adiponectin receptor agonist ALY688 in a mouse model of heart failure with reduced ejection fraction (HFrEF), and the mechanisms of cardiac remodeling leading to cardioprotection. Methods and results: Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricular pressure overload (PO), or sham surgery, with or without daily subcutaneous ALY688-SR administration. Temporal analysis of cardiac function was conducted via weekly echocardiography for 5 weeks and we observed that ALY688 attenuated the PO-induced dysfunction. ALY688 also reduced cardiac hypertrophic remodeling, assessed via LV mass, heart weight to body weight ratio, cardiomyocyte cross sectional area, ANP and BNP levels. ALY688 also attenuated PO-induced changes in myosin light and heavy chain expression. Collagen content and myofibroblast profile indicated that fibrosis was attenuated by ALY688 with TIMP1 and scleraxis/periostin identified as potential mechanistic contributors. ALY688 reduced PO-induced elevation in circulating cytokines including IL-5, IL-13 and IL-17, and the chemoattractants MCP-1, MIP-1β, MIP-1alpha and MIP-3α. Assessment of myocardial transcript levels indicated that ALY688 suppressed PO-induced elevations in IL-6, TLR-4 and IL-1β, collectively indicating anti-inflammatory effects. Targeted metabolomic profiling indicated that ALY688 increased fatty acid mobilization and oxidation, increased betaine and putrescine plus decreased sphingomyelin and lysophospholipids, a profile indicative of improved insulin sensitivity. Conclusion: These results indicate that the adiponectin mimetic peptide ALY688 reduced PO-induced fibrosis, hypertrophy, inflammation and metabolic dysfunction and represents a promising therapeutic approach for treating HFrEF in a clinical setting.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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