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

doi:10.1016/j.biopha.2023.116119

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

Biomed Pharmacother. 2024 Feb:171:116119. doi: 10.1016/j.biopha.2023.116119. Epub 2024 Jan 4.

Authors

Affiliations

¹ Department of Biology, York University, Toronto, ON, Canada.
² School of Kinesiology and Health Science, York University, Toronto, ON, Canada.
³ Faculty of Dentistry, University of Toronto, Toronto, ON M5S3E2, Canada.
⁴ Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
⁵ Department of Chemical Engineering and Applied Chemistry; University of Toronto, Toronto, ON M5S 3E5, Canada.
⁶ 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.
⁷ 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.
⁸ Allysta Pharmaceuticals Inc. Bellevue, WA, USA.
⁹ Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
¹⁰ Department of Biology, York University, Toronto, ON, Canada. Electronic address: gsweeney@yorku.ca.

PMID: 38181714
DOI: 10.1016/j.biopha.2023.116119

Abstract

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.

Keywords: Adiponectin; Fibrosis; Heart failure; Inflammation; Metabolism; Therapeutic.

MeSH terms

Adiponectin / metabolism
Animals
Fibrosis
Heart Failure* / metabolism
Humans
Mice
Mice, Inbred C57BL
Myocytes, Cardiac
Receptors, Adiponectin / metabolism
Stroke Volume
Ventricular Remodeling

Substances

Adiponectin
Receptors, Adiponectin