Cell-specific actions of interleukin (IL)-1 in the pressure-overloaded myocardium

• Applicant: Privatdozentin Dr. Izabela Tuleta
• Subject Area: Cardiology, Angiology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433385026

Cardiac pressure overload is the dominant pathophysiologic perturbation in many conditions associated with heart failure, including hypertension and aortic stenosis. Pressure overload triggers an inflammatory response, stimulating secretion of cytokines that modulate phenotype and function of all myocardial cell types. The pleiotropic and multifunctional pro-inflammatory cytokine interleukin (IL)-1 is markedly upregulated in pressure-overloaded hearts and may play an important role in the pathogenesis of heart failure, but may also stimulate protective pathways. Despite the availability of agents targeting the IL-1 system, implementation of IL-1 inhibition in patients with heart failure is hampered by the lack of knowledge on the cell-specific actions of IL-1 that may modulate inflammatory, pro-apoptotic, fibrogenic and angiogenic responses in the pressure-overloaded myocardium. The overarching goal of this proposal is to dissect cell-specific IL-1-mediated actions on cardiomyocytes, fibroblasts and macrophages in the pressure overloaded heart. We will use the Cre-lox system to generate mice with cardiomyocyte- fibroblast or macrophage-specific loss of the type I IL-1 receptor (IL-1RI), the only signaling receptor for IL-1alpha and IL-1beta. Cell-specific IL-1RI knock-out (KO) mice will undergo transverse aortic constriction protocols to recapitulate the pathophysiology of left ventricular pressure overload. In mice with cardiomyocyte-, fibroblast- and macrophage-specific loss of IL-1RI the effects of IL-1 signaling disruption on cardiac structure and function will be tested by echocardiography and hemodynamic monitoring. Molecular, proteomic and histopathologic endpoints will be studied to investigate the role of cell-specific IL-1 signaling in hypertrophy, fibrosis, inflammatory activation and matrix remodeling. Cell biological assays will be used to dissect the mechanisms of IL-1 actions using gain- and loss-of-function approaches. The proposed studies will greatly contribute to the understanding of the IL-1 signaling in heart failure, identifying protective and detrimental cell-specific actions. These insights will be used to design rational therapeutic approaches targeting the IL-1 system.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Nikolaos Georgios Frangogiannis