Cardioprotective Effects of S-Nitrosothiols in Ischemia- Reperfusion: Role for Mitochondria and Calcium Channels

Abstract

The most important clinical consequence of coronary disease is acute myocardial infarction caused by an occlusion that limits the irrigation to the heart. Although the gold standard treatment is to restore blood flow, this reperfusion causes inherent damage by increasing the size of the infarcted area primarily through the opening of the mitochondrial permeability transition pore (MPTP). The cardioprotective effect of nitric oxide (NO) has been described to operate through S-nitrosylation of several important proteins in the cardiomyocytes such as the calcium channels RyR2 and the L-type Ca 2+ channel and mitochondrial proteins, including the MPTP. In this sense, an attractive strategy to prevent the ischemia-reperfusion damage is to increase the bioavailability of endogenous Snitrosothiols. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of NO through denitrosylation, which would limit the cardioprotective effect of NO. Although inhibition of GSNOR has been studied in different organs, its effects on myocardial reperfusion have not yet been fully elucidated. In this chapter, we review the pathophysiology underlying myocardial reperfusion injury and the opening of the MPTP along with the cardioprotective role of S-nitrosothiols and the potential role for GSNOR.

Facilitating Nitrite-Derived S-Nitrosothiol Formation in the Upper Gastrointestinal Tract in the Therapy of Cardiovascular Diseases

“…Interestingly, mitochondria-targeted S-nitrosothiol inhibits mitochondrial complex I in ischemic tissue reperfusion, preventing the formation of free radicals, thus protecting the heart against post-myocardial infarction heart failure [ 221 ]. It is now becoming clear that S-nitrosation mechanisms leading to cardioprotection involve the S-nitrosation or transnitrosation of mitochondrial proteins, as previously detailed [ 223 , 224 , 225 ]. However, while previous studies have shown a decreased infarcted area after ischemia and improved heart functionality [ 223 , 224 , 225 ], it remains to be proved whether oral nitrite-induced nitrosation results in clinical protection.…”

“…It is now becoming clear that S-nitrosation mechanisms leading to cardioprotection involve the S-nitrosation or transnitrosation of mitochondrial proteins, as previously detailed [ 223 , 224 , 225 ]. However, while previous studies have shown a decreased infarcted area after ischemia and improved heart functionality [ 223 , 224 , 225 ], it remains to be proved whether oral nitrite-induced nitrosation results in clinical protection.…”

Nitric Oxide and S-Nitrosylation in Cardiac Regulation: G Protein-Coupled Receptor Kinase-2 and β-Arrestins as Targets

“…S-nitrosylated cytochrome c oxidase [ 80 ] and F1F0ATPase [ 81 ] has inhibited activity resulting in diminished oxygen and ATP consumption, respectively. SNO of mitochondrial permeability transition pore (MPTP) blocks its opening and thus prevents mitochondrial dysfunction leading to cardiomyocyte death [ 82 ]. On the other hand, SNO augments parkin [ 83 ] and α-ketoglutarate dehydrogenase [ 71 ] activities resulting in the modulation of mitochondrial degradation and prevention of oxidative stress.…”

Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion

“…In general, S-nitrosothiols have shown to be cardioprotective [ 18 ] and several lines of evidence support this notion [ 19 ]. First, NO donors and small S-nitrosothiols were reported to reduce cardiac damage [ 20 , 21 ].…”