Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis

Abstract

Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury. Whether these species exert anti-arrhythmic effects in the acute phase of myocardial ischemia has not been investigated so far. Herein, we demonstrate that pretreatment of mice with 9- and 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA) significantly reduced the susceptibility to develop acute ventricular tachycardia (VT). Accordingly, epicardial mapping revealed a markedly enhanced homogeneity in ventricular conduction. NO2-OA treatment of isolated cardiomyocytes lowered the number of spontaneous contractions upon adrenergic isoproterenol stimulation and nearly abolished ryanodine receptor type 2 (RyR2)-dependent sarcoplasmic Ca2+ leak. NO2-OA also significantly reduced RyR2-phosphorylation by inhibition of increased CaMKII activity. Thus, NO2-OA might be a novel pharmacological option for the prevention of VT development.

Glutathione in Protein Redox Modulation through S-Glutathionylation and S-Nitrosylation

“…Although the in vivo mechanisms of formation of NO 2 -FAs are not yet fully understood, it has been shown that they proceed with the participation of NO and its derivatives. On the other hand, NO 2 -FAs have been shown to be capable of releasing NO and carrying out post-translational protein modifications through nitroalkylation [ 141 , 142 , 143 , 144 ], due to which NO 2 -FAs (e.g., nitro-oleic and nitro-linoleic acids) are able to provide vasodilating, antioxidant, and anti-inflammatory action, which are important for the physiology of animals and plants, promoting the activation of defense mechanisms in stressful conditions.…”

Nitro Fatty Acids (NO2-FAs): An Emerging Class of Bioactive Fatty Acids

“…The way NO 2 -OA decreases the levels of Lp-PLA 2 biomarker in blood can be explained by the simultaneous downregulation of cytokines, causing inflammation and the enchancement of SuperOxide Dismutase (SOD) activity. NO 2 -OA may be an alternative as a therapeutic compound for encountering Ventricular Tachykardia (VT), since a murine model demonstrated significantly reduced chance of appearing VT, after NO 2 -OA was administrated [43].…”

Regulatory mechanism of calcium/calmodulin‑dependent protein kinase II in the occurrence and development of ventricular arrhythmia (Review)

“…According to mechanistic studies (10,11), the occurrence and development of VA events during the acute phase of AMI can be attributed to diastolic Ca 2+ leak and disturbed Ca 2+ homeostasis. This can be induced by enhanced sympathetic tone and is accompanied by the formation of reentry circuits, further increasing vulnerability to VT (12). Calcium/calmodulin-dependent protein kinase II (CaMKII) is a versatile serine/threonine kinase that is found widely in muscle, nerve and immune tissues (13).…”

“…The serine 2814 site of RyR 2 is phosphorylated upon CaMKII activation, which occurs when the release of Ca 2+ stored in the diastolic SR abnormally increases (31,(42)(43)(44). Abnormally released Ca 2+ propagates along adjacent RyR S on the SR and activates them to trigger further Ca 2+ release (8,12). Increased intracellular Ca 2+ concentrations can participate in the regulation of Na v channel function through CaMKII activation, thereby adjusting the flow of Na + (45).…”