PhD grants "Post-infarct cardiac remodeling and purinergic signaling" (SSBCV)

• 36 months doctoral funding (October 2021 to September 2024)
• Keywords

Myocardial infarction, Purinergic signaling, cardiac remodeling, sterile inflammation

• Profile and skills required

We are looking for a student that show great motivation and seriousness, who can show initiative and display deductive skills.

He/she should be competent in cell culture and the main techniques of molecular biology (western blots, Elisa, PCR, immunofluorescence) and have a good english level;

• Project description

Cardiovascular diseases are the most frequent cause of mortality worldwide. While the prognosis of acute myocardial infarction decreases with the improvements in medical therapy and reperfusion strategies, some patients experience adverse cardiac remodeling responsible from decreased prognosis and subsequent heart failure. One of the main hypothesis is the maintenance of a local pro-inflammatory environment that would impair healing. Among the actors of sterile inflammation associated to myocardial infarction, purinergic receptors P2 are of interest because of their identification in heart and their implication either in myocardial infarction or remodeling or heart failure.

Our objective is to identify the purinergic signature associated with post-infarct adverse cardiac remodeling and consider modulation of these receptors to reverse this pathologic phenomenon.

This work is scheduled in 2 steps.

The first step will be to identify, in patients followed in Tours University Hospital for anterior acute myocardial infarction who experienced adverse cardiac remodeling, the purinergic signature deemed responsible for their pejorative evolution, and to compare this signature to that of equivalent patients with a successful post-infarct evolution. This can be done thanks to an ongoing cohort on myocardial infarction in Tours University Hospital.

The second step consists in evaluating in vitro the impact of this specific purinergic signature on inflammatory cells (dendritic cells alone or in co-culture with T lymphocytes) regarding the polarization of the inflammatory response, and on cardiac cells, in particular cardiofibroblasts and vascular cells (endothelial cells and smooth muscle cells) who are the actors of adverse cardiac remodeling.

• References

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2. Certal M, Vinhas A, Pinheiro AR, et al. Calcium signaling and the novel anti-proliferative effect of the UTP-sensitive P2Y11 receptor in rat cardiac myofibroblasts. Cell Calcium 2015;58:518–533.

3. Cohen R, Shainberg A, Hochhauser E, et al. UTP reduces infarct size and improves mice heart function after myocardial infarct via P2Y2 receptor. Biochem. Pharmacol. 2011;82:1126–1133.

4. Golan O, Issan Y, Isak A, Leipziger J, Robaye B, Shainberg A. Extracellular nucleotide derivatives protect cardiomyocytes against hypoxic stress. Biochem. Pharmacol. 2011;81:1219–1227.

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6. Lefort C, Benoist L, Chadet S, et al. Stimulation of P2Y11 receptor modulates cardiac fibroblasts secretome toward immunomodulatory and protective roles after Hypoxia/Reoxygenation injury. J. Mol. Cell. Cardiol. 2018;121:212–222.

7. Mezzaroma E, Toldo S, Farkas D, et al. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc. Natl. Acad. Sci. U. S. A. 2011;108:19725–19730.

8. Takahashi M. Role of NLRP3 Inflammasome in Cardiac Inflammation and Remodeling after Myocardial Infarction. Biol. Pharm. Bull. 2019;42:518–523.

9. Wihlborg A-K, Balogh J, Wang L, et al. Positive inotropic effects by uridine triphosphate (UTP) and uridine diphosphate (UDP) via P2Y2 and P2Y6 receptors on cardiomyocytes and release of UTP in man during myocardial infarction. Circ. Res. 2006;98:970–976.

10. Benoist L, Chadet S, Genet T, et al. Stimulation of P2Y11 receptor protects human cardiomyocytes against Hypoxia/Reoxygenation injury and involves PKCε signaling pathway. Sci. Rep. 2019;9:11613.

11. Bourguignon T, Espitalier F, Pantaleon C, et al. Bioprosthetic mitral valve replacement in patients aged 65 years or younger: long-term outcomes with the Carpentier-Edwards PERIMOUNT pericardial valve. Eur. J. Cardio-Thorac. Surg. Off. J. Eur. Assoc. Cardio- Thorac. Surg. 2018;54:302–309.

12. Chadet S, Ivanes F, Benoist L, et al. Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells. J. Immunol. Baltim. Md 1950 2015;195:651–660.

13. Torrado J, Cain C, Mauro AG, et al. Sacubitril/Valsartan Averts Adverse Post-Infarction Ventricular Remodeling and Preserves Systolic Function in Rabbits. J. Am. Coll. Cardiol. 2018;72:2342–2356.a

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