Novel signaling pathways of vascular calcification

• Applicant: Privatdozentin Ioana Alesutan, Ph.D.
• Subject Area: Cardiology, Angiology ; Nephrology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 319321725

Medial vascular calcification is an active process, mediated by vascular smooth muscle cells. This process is closely associated with an increased risk of cardiovascular events and is especially involved in the high cardiovascular mortality of chronic kidney disease patients. Until now, no established therapeutic strategy exists to reduce vascular calcification. This project aims to identify unknown mechanisms underlying the process of vascular calcification, which may be suitable as therapeutic targets.Aim of the project is to investigate the role of Phosphoinositide 3-kinase (PI3K)-dependent signaling pathways during vascular calcification. It is hypothesized that increased ceramide formation occurs during vascular calcification which selectively activates the PI3K-serum and glucocorticoid-regulated kinase 1 (Sgk1) pathway. Pilot-studies suggest that inhibition of this pathway is able to ameliorate vascular calcification. Therefore, the activation and the functional role of signaling molecules of the hypothetical Ceramid-PI3K-Sgk1 pathway will be investigated. Translation of these observations to human patients will be improved by validation experiments. Furthermore, the pharmacological inhibition of key factors of the identified signaling pathways will be evaluated as therapeutical target to reduce vascular calcification. These studies will be conducted in primary human and mouse vascular smooth muscle cells as well as murine aortic ring explants. Key factors of the identified signaling pathways will be validated in coronary artery biopsies of patients with reduced renal function. The role of this signaling pathway during vascular calcification in-vivo will be investigated in the vitamin-D3 overload and 5/6 nephrectomy animal models of vascular calcification.These studies can provide important knowledge about unknown signaling pathways of medial vascular calcification. These signaling pathways could be of crucial importance as pharmacological targets. Therefore these observations may serve as the basis of a therapeutic strategy to reduce the burden of vascular calcification.

• DFG Programme: Research Grants
• International Connection: Austria
• Co-Investigators: Professor Dr. Burkert Pieske; Dr. Jakob Völkl