Investigating the mechanisms of nitrite-mediated cardioprotection

R Medicine > RC Internal medicine

Hayes, Rosie May ; Madhani, Melanie

University:University of Birmingham

Department:School of Clinical and Experimental Medicine, Centre for Cardiovascular Sciences

关键词: R Medicine;    RC Internal medicine;   

Others  :  http://etheses.bham.ac.uk//id/eprint/7003/1/Hayes16MSc.pdf

来源: University of Birmingham eTheses Repository

【 摘 要 】

Nitrite is able to elicit cardioprotection against myocardial IRI when administered as a preconditioning agent. Activation of the classical NO-sGC-cGMP-PKG pathway under hypoxic and/or acidic conditions has been implicated in this protection but the exact mechanism remains unclear. Herein, we investigated whether nitrite mediates cardioprotection by (1) PKG1α oxidation and/or (2) ALDH2 pathway. Using an isolated Langendorff mouse model of IRI, nitrite (100μM) was administered as a preconditioning agent in (1) PKG1α WT and Cys42Ser KI mice or (2) ALDH2 WT and KO mice.We demonstrate that nitrite improves cardiac function (LVDP; p<0.01; n=8-12) and coronary flow rate (CFR; p<0.001; n=8-12) post-IRI via the PKG1α oxidation pathway. However, we observed no significant difference following nitrite treatment in the PKG1αWT and KI mice (p>0.05; n=8-12), thus suggesting a dual mechanism involving the classical pathway in the cardiomyocytes. In contrast, we offer evidence to support ALDH2 involvement in nitrite-mediated improvements in CFR (p<0.001; n=7-11) and suggest it may also be involved in cardioprotection.The study provides novel evidence supporting the involvement of both the PKG1α oxidation and ALDH2 pathways in nitrite-mediated effects at the level of the cardiac microvasculature and cardiomyocytes in a murine model of myocardial IRI.