Supervisors:

prof. dr hab. Stefan Chłopicki
dr Grzegorz Kwiatkowski

Jagiellonian Centre for Experimental Therapeutics

Project description:

Rapid exacerbation of heart failure, also known as acute decompensated heart failure, is a growing medical problem with acute decompensated heart failure, representing 2% of all hospitalization in Europe and being the leading cause of hospitalization for people over 65 years. Given the absence of effective treatment, and the low effectiveness of ‘classical’ pharmacological treatments used in heart failure, there is unmet need for to explore other mechanisms driving the acute decompensation in heart failure.

Post-translational modifications involving O-GlcNAcylation is a recently discovered mechanism that play an important role in the regulation of cardiac metabolism [1] but its role in the regulation of vascular function is not well-know. In this project vascular effects of pharmacology of O-GlcNAcylation will be studied in the context of acute decompensation of hear failure as O-GlcNAcase inhibition improve the phenotype of acute decompensated heart failure and this effect could be in part mediated by vascular effects in coronary circulation.

On the methodological level this research project is based on interdisciplinary, state-of-the art methodologies used in our recent studies including e.g.; Magnetic Resonance Imaging – MRI to assess cardiac and endothelial function in vivo in mice, or the isolated perfused heart [2-5], vascular preparations for functional and metabolomic studies of peripheral vessels [6] complemented with proteomic and O-GlcNAcylation studies. Finally project will involve characterization of in vitro phenotype of primary endothelial cells isolated from mice with decompensated heart failure. The research is carried out in the frame of ERA4Health Joint Transnational project entitled “O-GlcNAcase Inhibition in Acute Decompensated Heart Failure (GANDHI)” realized at JCET in the close collaboration with partners from Rouen University (leader), Institut Pasteur in Lille, and Maastricht University, Cardiovascular Research Institute Maastricht (CARIM).

References:

[1] R. Gélinas, et a., AMP-Activated Protein Kinase and O-GlcNAcylation, Two Partners Tightly Connected to Regulate Key Cellular Processes. Front Endocrinol (Lausanne), 2018 Sep 13:9:519. https://pubmed.ncbi.nlm.nih.gov/30271380/

[2] G.Kwiatkowski et al., MRI-based in vivo detection of coronary microvascular dysfunction before alterations in cardiac function induced by short-term high-fat diet in mice. Sci Rep 2021 Sep 23;11(1):18915. https://pubmed.ncbi.nlm.nih.gov/34556779/

[3] G.Kwiatkowski et al., Retrospectively gated ultrashort-echo-time MRI T1 mapping reveals compromised pulmonary microvascular NO-dependent function in a murine model of acute lung injury. NMR Biomed 2024 May;37(5):e5105. https://pubmed.ncbi.nlm.nih.gov/38225796/

[4] P. Efentakis et al., Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin. Basic Res Cardiol 2024 Mar 23. doi: 10.1007/s00395-024-01046-0. https://pubmed.ncbi.nlm.nih.gov/38520533/

[5] P.Berkowicz et al., Accelerated ageing and coronary microvascular dysfunction in chronic heart failure in Tgαq*44 mice. Geroscience ,2023 Jun;45(3):1619-1648. https://pubmed.ncbi.nlm.nih.gov/36692592/

[6] Karas A, et al., Functional deterioration of vascular mitochondrial and glycolytic capacity in the aortic rings of aged mice. Geroscience. 2024. https://pubmed.ncbi.nlm.nih.gov/38418756/