Adenosine A1 receptor activation increases myocardial protein S-nitrosothiols and elicits protection from ischemia-reperfusion injury in male and female hearts

Abstract

Nitric oxide (NO) plays an important role in cardioprotection, and recent work from our group and others has implicated protein S-nitrosylation (SNO) as a critical component of NO-mediated protection in different models, including ischemic pre- and post-conditioning and sex-dependent cardioprotection. However, studies have yet to examine whether protein SNO levels are similarly increased with pharmacologic preconditioning in male and female hearts, and whether an increase in protein SNO levels, which is protective in male hearts, is sufficient to increase baseline protection in female hearts. Therefore, we pharmacologically preconditioned male and female hearts with the adenosine A1 receptor agonist N6-cyclohexyl adenosine (CHA). CHA administration prior to ischemia significantly improved functional recovery in both male and female hearts compared to baseline in a Langendorff-perfused heart model of ischemia-reperfusion injury (% of preischemic function ± SE: male baseline: 37.5±3.4% vs. male CHA: 55.3±3.2%; female baseline: 61.4±5.7% vs. female CHA: 76.0±6.2%). In a separate set of hearts, we found that CHA increased p-Akt and p-eNOS levels. We also used SNO-resin-assisted capture with LC-MS/MS to identify SNO proteins in male and female hearts, and determined that CHA perfusion induced a modest increase in protein SNO levels in both male (11.4%) and female (12.3%) hearts compared to baseline. These findings support a potential role for protein SNO in a model of pharmacologic preconditioning, and provide evidence to suggest that a modest increase in protein SNO levels is sufficient to protect both male and female hearts from ischemic injury. In addition, a number of the SNO proteins identified with CHA treatment were also observed with other forms of cardioprotective stimuli in prior studies, further supporting a role for protein SNO in cardioprotection.

Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy

“…S-nitrosylation has been previously suggested to be protective, particularly in the setting of ischemic injury or other oxidative damage, shielding specific cysteine residues from irreversible oxidation (33). Nevertheless, excessive S-nitrosylation is thought to contribute to disease pathogenesis, as in neurodegenerative diseases, including Alzheimer's and Parkinson's diseases (34,35). In a similar fashion, increased S-nitrosylation has been linked to arrhythmias in focused studies examining RyRs in DMD muscles (21,22).…”

Mechanisms involved in adenosine pharmacological preconditioning-induced cardioprotection

“…Furthermore, adenosine preconditioning may trigger NOS phosphorylation to increase its activity, which subsequently increases NO production [ 30 ]. NO may increase nitrosylation of proteins to increase the levels of S-nitrosothiols, which helps in attenuating myocardial injury during ischemia reperfusion [ 48 ].…”

“…Moreover, there was an increase in the levels of S-nitrosothiols proteins, formed by NO-mediated nitrosylation of proteins. It suggests that adenosine may increase the production of NO to trigger cardioprotection [ 48 ].…”

“…Therefore, it may be proposed that activation of A 2B receptors activates PI3K to promote Akt phosphorylation, which in turn may decrease influx of inflammatory cells to prevent cardiac injury [ 38 ]. Recently, it has been reported that pretreatment with N6-cyclohexyladenosine (A 1 receptor agonist) significantly increases Akt phosphorylation in mouse heart to trigger cardioprotection against ischemia-reperfusion injury [ 48 ].…”

The Effectiveness of Preconditioning and Postconditioning With Adenosine in Prevention of Reperfusion Damage in Patients With St-Segment Elevation Myocardial Infarction

“…Известно, что в ус-ловиях острой ишемии и реперфузии активируется выработка эндогенного аденозина [7]. В настоящее время на поверхности кардиомиоцитов обнаружены четыре типа рецепторов к аденозину: A1, А2А, A2B и A3.…”