Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy

Jordan S F Chan¹, Seyed Amirhossein Tabatabaei Dakhili¹, Maria Areli Lorenzana-Carrillo², Keshav Gopal¹, Serena M Pulente³, Amanda A Greenwell¹, Kunyan Yang¹, Christina T Saed¹, Magnus J Stenlund¹, Sally R Ferrari¹, Indiresh A Mangra-Bala¹, Tanin Shafaati¹, Rakesh K Bhat⁴, Farah Eaton¹, Michael Overduin⁴, Sebastian Beck Jørgensen⁵, Gregory R Steinberg⁶, Erin E Mulvihill³, Gopinath Sutendra², John R Ussher⁷

Affiliations

¹ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada.
² Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada; Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada.
³ Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada.
⁴ Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
⁵ Bio Innovation Hub Transformational Research Unit, Novo Nordisk, Boston, MA 02142, USA.
⁶ Centre for Metabolism, Obesity, Diabetes Research, McMaster University, Hamilton, ON L8S 4K1, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
⁷ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada. Electronic address: jussher@ualberta.ca.

PMID: 39093701
DOI: 10.1016/j.celrep.2024.114573

Free article

Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy

Jordan S F Chan et al. Cell Rep. 2024.

Free article

. 2024 Aug 27;43(8):114573.

doi: 10.1016/j.celrep.2024.114573. Epub 2024 Jul 31.

Authors

Affiliations

¹ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada.
² Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada; Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G3, Canada.
³ Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada.
⁴ Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
⁵ Bio Innovation Hub Transformational Research Unit, Novo Nordisk, Boston, MA 02142, USA.
⁶ Centre for Metabolism, Obesity, Diabetes Research, McMaster University, Hamilton, ON L8S 4K1, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
⁷ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada. Electronic address: jussher@ualberta.ca.

PMID: 39093701
DOI: 10.1016/j.celrep.2024.114573

Abstract

Growth differentiation factor 15 (GDF15) is a peptide with utility in obesity, as it decreases appetite and promotes weight loss. Because obesity increases the risk for type 2 diabetes (T2D) and cardiovascular disease, it is imperative to understand the cardiovascular actions of GDF15, especially since elevated GDF15 levels are an established biomarker for heart failure. As weight loss should be encouraged in the early stages of obesity-related prediabetes/T2D, where diabetic cardiomyopathy is often present, we assessed whether treatment with GDF15 influences its pathology. We observed that GDF15 treatment alleviates diastolic dysfunction in mice with T2D independent of weight loss. This cardioprotection was associated with a reduction in cardiac inflammation, which was likely mediated via indirect actions, as direct treatment of adult mouse cardiomyocytes and differentiated THP-1 human macrophages with GDF15 failed to alleviate lipopolysaccharide-induced inflammation. Therapeutic manipulation of GDF15 action may thus have utility for both obesity and diabetic cardiomyopathy.

Keywords: CP: Metabolism; GDF15; diabetic cardiomyopathy; diastolic dysfunction; inflammation; obesity; type 2 diabetes.

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Conflict of interest statement

Declaration of interests G.R.S. has received research funding through McMaster University from Esperion Therapeutics, Nestle, Merck, Cambrian Biosciences, Novo Nordisk, Poxel Pharmaceuticals, and Espervita Therapeutics; has received honoraria and/or consulting fees from AstraZeneca, Cambrian Biosciences, Eli-Lilly, Esperion Therapeutics, Fibrocor Therapeutics, Poxel Therapeutics, Novo Nordisk, and Merck; and is a founder and shareholder of Espervita Therapeutics. S.B.J. is an employee of Novo Nordisk A/S, a pharmaceutical company producing and selling medicine for the treatment of chronic diseases such as diabetes and obesity.

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Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy

Affiliations

Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy

Authors

Affiliations

Abstract

Conflict of interest statement

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Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous