Roles and relationship of gasotransmitters hydrogen sulfide nitric oxide in myocardial infarction

Abstract

Hydrogen sulfide (H2S) and nitric oxide (NO) are gasotransmitters endogenously synthesized in the body, sharing several common roles such as vasodilation. Additionally, both are implicated in the disease progression of myocardial infarction (MI), which will be examined in this study. Furthermore, several works have investigated their interaction in the vascular system, but due to the disparity in outcomes observed, their relationship is far from clear. Thus far, the interplay between H2S and NO in the cardiovascular system has not been researched on. For this thesis, we aim to elucidate the roles and relationship of H2S and NO in MI, and shed light on the mechanisms involved.<br>In the first study, S-allylcysteine (SAC) is proposed to be a novel H2S donor as it exerted cardioprotection through a CSE (H2S-synthesizing enzyme)/H2S-related pathway. Pre-treatment with SAC before MI induction lowered mortality and reduced infarct size. This was accompanied by an increase in left ventricular (LV) H2S production and plasma H2S concentration. Co-treatment with propargylglycine (PAG; CSE inhibitor) which blocked H2S production and lowered plasma H2S concentration was shown to abrogate the improvements in survival and infarct. Furthermore, SAC increased NO content in the LV and plasma, implicating NO involvement in SAC-mediated cardioprotection.<br>In the next study, sildenafil brought about cardioprotection in MI via a NO-related pathway with the concomitant involvement of H2S. Sildenafil improved survival and attenuated infarct size. This was via a NOS/NO pathway as protein and gene expressions of eNOS, nNOS and iNOS were drastically upregulated with an associated enhancement in LV and plasma NO levels. Interestingly, sildenafil also stimulated CSE activity by increasing H2S production in the heart without affecting CSEb s protein expression, providing yet another evidence for the interaction between H2S and NO.<br>The third study examined this crosstalk on a common platform using both donors and inhibitors of H2S and NO in in vivo MI models. NaHS and molsidomine attenuated infarct enlargement and improved survival whilst inhibitors of CSE and NOS exacerbated these. Crosstalk is evidently present between H2S and NO. Firstly, NaHS increased LV and plasma NO levels due to an upregulation of eNOS and iNOS gene and protein expressions. Consistent stimulation of NOS/NO pathway by NaHS may involve HIF as NaHS upregulated HIF-1 protein expression drastically. This will be further examined in the next study. Secondly, blockade of H2S production with PAG resulted in higher NO levels in both LV and plasma. This may be due to an increment in NOS activities as protein expressions were unaltered. Thirdly, NOS inhibitor L-NAME increased CSE protein expression, which was accompanied by an increase in LV H2S production. <br>Transcription factor HIF-1 plays a pivotal role in initiating the transcription of hypoxia-sensitive genes to improve cellular adaptation to hypoxia. During hypoxia, NaHS enhanced HIF-1 protein expression and transcriptional activity in cardiac cells. Moreover, following NaHS treatment, HIF-1 activation upregulated downstream target iNOS and increased NO production. Additionally, numerous studies have implicated PI3K/Akt participation during hypoxia to mediate HIF-1N1 activation. Hence, its involvement was determined. NaHS-pretreated hypoxic cells had higher Akt and eNOS phosphorylations, which were abrogated when PI3K inhibitors were applied, indicating PI3K/Akt pathway involvement in this mode of cardioprotection. Furthermore, it was determined that this pathway lies upstream of HIF-1N1. <br>In conclusion, this study provided evidence for a cardioprotective role of H2S and NO, and support for their crosstalk in MI. Furthermore, we elucidated that H2S exerted its cardioprotection by enhancing HIF-1N1 activation and its downstream target iNOS with the participation of PI3K/Akt/eNOS pathway.<br>