JCET

In the 17th edition of the SONATA 17 competition announced by the National Science Center in Krakow, PhD Agnieszka Kij is the second scientist from the Jagiellonian Centre for Experimental Therapeutics (JCET) which to receive funding for research . The Doctor Kij will run a project entitled “In the search of specific oxylipin fingerprint reflecting the development of endothelial dysfunction with the use of non-targeted and targeted lipidomics”.

Oxylipins are biologically active lipid mediators encompassing oxygenation products of polyunsaturated fatty acids (PUFAs) including arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Oxylipins such as AA-derived eicosanoids participate mainly in pro-inflammatory response (e.g., prostaglandins), with the exception of vasoprotective prostacyclin (PGI2). In recent years, an increasing attention has been paid to a novel class of AA-, EPA- and DHA-derived oxylipins referred as specialized pro-resolving mediators (SPMs; e.g., lipoxins LX, maresins MaR, resolvins RvE and RvD), that govern the resolution of inflammation and promote tissue regeneration. One can assume, that unresolved inflammation resulted from failed lipid mediator class switching from pro-inflammatory eicosanoids to SPMs can contribute to chronic vascular inflammation, and consequently to coronary and systemic endothelial dysfunction (ED). Despite the growing knowledge on lipid-dependent molecular mechanisms involved in endothelial dysfunction development, the pattern and time-frame of oxylipin alterations linked specifically to hyperlipidaemia- and age-induced coronary and systemic endothelial dysfunction, that could be helpful for early diagnosis, prevention and treatment of ED and cardiovascular diseases (e.g., atherosclerosis), have not been characterized.

In the 17th edition of the SONATA 17 competition announced by the National Science Center in Krakow, three scientists from the Jagiellonian Centre for Experimental Therapeutics (JCET) were among the winners. Today we present the assumption of the project of Dr. Eng. Marta Pacia, “Multimodal approach for a comprehensive assessment of (dys)functional endothelial phenotype in isolated blood vessels”.

Sodium-glucose co-transports 2 inhibitors (SGLT2-I) are a new generation of drugs for diabetes (including empagliflozin or dapagliflozin), however, their spectrum of action goes far beyond the systemic glucose reduction, and theirs protective effect on the ECs is postulated, both in hyperglycaemic conditions and in inflammatory state of the vasculature. Since the mechanism of action of SGLT2-I remains elusive so far, in this project I propose the development of a unique methodology aimed to uncover alterations of chemical, biological, nanostructural, and functional properties of activated/dysfunctional ECs in isolated blood vessels, which brings us closer to unravelling the mystery of how SGLT2-I actually work on the vascular wall. This first stage of the project includes the application of the developed research methodology to characterize the effect of SGLT2-I on inflammation- or hyperglycemia-activated endothelium, while the second stage includes the application of the developed research methodology to reveal the mechanisms of action of SGLT2-I and to verify the therapeutic efficiency of SGLT2-I to reverse endothelial dysfunction.

The National Science Center in Krakow has published the results of the MAESTRO 13 competition. The thirteenth edition turned out to be lucky for the Director of the Jagiellonian Centre for Experimental Therapeutics (JCET), Professor Stefan Chłopicki, who received funding for the project: Metabolic reprogramming in age-dependent endothelial dysfunction and vascular stiffness; novel mechanism of “inflamm-ageing”.

Ageing is the major risk factor of various diseases including cardiovascular diseases. Chronic, sterile, low-grade inflammation observed in older organism that have been recently named “inflamm-ageing”, results in accelerated development of endothelial dysfunction  and large arteries stiffness. These two phenotypes;  systemic endothelial dysfunction and increased stiffness of large arteries, can be measured in clinical conditions, and predict morbidity and mortality of cardiovascular diseases. Accordingly, the improvement in endothelial function and artery stiffness can have therapeutic effects. However, mechanisms involved in inflamm-ageing are not clear.

In the present project, we hypothesize that accelerated age-dependent dysfunctional vasculature in E3L.CETP mice might be explained by vascular metabolic reprogramming that could contribute to vascular inflamm-ageing and  subsequently to persistent vascular inflammation, enhanced susceptibility of vascular wall to inflammatory insults, and to endothelial dysfunction and arterial stiffness. We aim to characterize metabolic signature of inflamm-ageing in murine models, and in particular to define the mechanisms and importance of metabolic reprogramming in the development of age-dependent endothelial dysfunction in large arteries and in coronary microcirculation, as well as in arterial stiffness. Project will be based on interdisciplinary, state-of-the art methodologies including e.g.; Magnetic Resonance Imaging – MRI to assess endothelial function in vivo in mice, microfluidic device to characterize in vitro primary endothelial cells isolated from mice, and targeted and non-targeted metabolomics to define metabolic pathways of dysfunctional endothelium and vascular wall ex vivo.