Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug

Abstract

Low dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of cyclophilin D, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results.

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

“…On the other hand, the CyA analogs alisporivir/debio-025 [238], sanglifehrin A [234,312] and (NIM811) [240,313] are also showing progress against IRI in the myocardium, liver, and brain in animal models. Although not a CyA analog, it has been recently shown that the classic vasodilator nitroglycerine (glyceryl trinitrate) also inhibits CyD via S -nitrosation, and therefore limits I/R-driven myocardial infarction in rabbits [314].…”

The Role of Gasotransmitters (No and H2s) in Defence Mechanisms Against Postischemic Liver Injuries

“…Повышение сродства гемоглобина к кислороду (СГК) в крови и уменьшение потока кислорода в ткани при реперфузии под влиянием нитроглицерина и нитропруссида натрия способствовало снижению в печени уровня диеновых конъюгатов (ДК), малонового диальдегида и оснований Шиффа, указывая на уменьшение активности свободнорадикальных процессов перекисного окисления липидов (ПОЛ). Одновременно в печени под влиянием доноров NO в конце реперфузии происходит нормализация уровня α-токоферола, ретинола и активности каталазы Показано, что протективный эффект нитроглицерина наблюдается в условиях ишемии-реперфузии сердца [10]. Защитное действие доноров NO при ИРП можно обосновать улучшением условий микроциркуляции и снижением синтеза молекул межклеточной адгезии [11].…”

Interplay of the red blood cell and vascular endothelial nitric oxide synthase system to combat cardiac complications of anemia

“…The general role of • NO for cardioprotection is also supported by numerous reports on loss of cardioprotective effects of • NO or • NO-related therapies upon treatment with the inhibitor of all NOS isoforms, N G -nitro-l-arginine methyl ester (l-NAME) (only citing a few [4,6,15,26]). Also exogenous administration of tetrahydrobiopterin (BH 4 ), an essential cofactor for eNOS function, improved ischemic damage in isolated hearts subjected to I/R [27,29].…”

“…The cardioprotective properties of eNOS and • NO are widely accepted and were extensively reviewed in the past [9,24] and redefined in recent years [3]. The cardioprotection afforded by • NO (e.g., from nitrovasodilators such as nitroglycerin [13]) largely depends on the prevention of mitochondrial permeability transition pore (mPTP) opening via S-nitros(yl)ation of the mPTP regulator cyclophilin D during reperfusion [4]. This mechanism reflects a major detrimental process in ischemia/reperfusion (I/R) damage leading to excessive reactive oxygen species (ROS) formation/release as well as onset of apoptotic cell death [7,21].…”

“…Of note, genetic deficiency in neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) did not show this aggravated ischemic damage; in contrast, iNOS knockout mice were rather protected against ischemic damage [25]. Also, the cardioprotective effects of nitroglycerin upon myocardial infarction were lost in eNOS knockout mice [4]. In addition, a cardiomyocyte-specific overexpression of eNOS largely prevented I/R injury [8].…”