Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis

Abstract

Nitro-oleic acid (NO2-OA), a nitric oxide (NO)- and nitrite (NO2−)-derived electrophilic fatty acid metabolite, displays anti-inflammatory and anti-fibrotic signaling actions and therapeutic benefit in murine models of ischemia-reperfusion, atrial fibrillation, and pulmonary hypertension. Muscle LIM protein-deficient mice (Mlp−/−) develop dilated cardiomyopathy (DCM), characterized by impaired left ventricular function and increased ventricular fibrosis at the age of 8 weeks. This study investigated the effects of NO2-OA on cardiac function in Mlp−/− mice both in vivo and in vitro. Mlp−/− mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneous osmotic minipumps. Wildtype (WT) littermates treated with vehicle served as controls. Mlp−/− mice exhibited enhanced TGFβ signalling, fibrosis and severely reduced left ventricular systolic function. NO2-OA treatment attenuated interstitial myocardial fibrosis and substantially improved left ventricular systolic function in Mlp−/− mice. In vitro studies of TGFβ-stimulated primary cardiac fibroblasts further revealed that the anti-fibrotic effects of NO2-OA rely on its capability to attenuate fibroblast to myofibroblast transdifferentiation by inhibiting phosphorylation of TGFβ downstream targets. In conclusion, we demonstrate a substantial therapeutic benefit of NO2-OA in a murine model of DCM, mediated by interfering with endogenously activated TGFβ signaling.

Nitro-Oleic Acid-Mediated Nitroalkylation Modulates the Antioxidant Function of Cytosolic Peroxiredoxin Tsa1 during Heat Stress in Saccharomyces cerevisiae

“…Therefore, in yeast, only OA or PA would be available to react with RNS to generate the corresponding NO 2 -FAs. We searched nitrated oleic acid because this molecule had been detected in other species, and its implications in cell signaling processes had been previously described [52][53][54][55][56]. In line with this, the NO 2 -OA levels in S. cerevisiae in the non-stress situation were 0.038 ± 0.01 pmoles/g FW, which fall within the range with the concentration of other signaling molecules.…”

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

“…Human atherosclerosis is a typical vessel-derived disease, so NO 2 -FAs could be an alternative therapy in that case. NO 2 -OA has also been reported by Braumann et al that can attenuate myocardial fibrosis in a murine model of dilated cardiomyopathy (DCM) [37].…”

Fatty acids and risk of dilated cardiomyopathy: A two-sample Mendelian randomization study

“…In the PREDIMED trial conducted by Guasch-Ferré et al MUFA intake was found to have a significant correlation with total cardiovascular disease (CVD) risk as a protective factor (HR = 0.630, 95%CI: 0.430–0.940) ( 38 ). This protection may be mediated by the synthesis of the endogenous signaling mediator NO 2 -OA ( 17 ) and hydroxylation to hydroxyl fatty acids in response to metabolic disturbances and increased inflammatory stress in the DCM ( 17 ). In general, these positive correlation results are consistent with ours, suggesting the causal effect of oleic acid on DCM.…”

“…According to the findings of DCM metabolomics studies, linoleic acid could be used as the primary biomarker to measure the effectiveness of DCM treatment, and hydroxyl fatty acid esters were potential biomarkers to identify DCM ( 16 ). Additionally, Nitro-oleic acid (NO 2 -OA), a signaling mediator produced naturally by reacting oleic acid with nitrogen dioxide (NO 2 ), was created as a therapeutic agent for fibrotic and inflammatory diseases and has been proven effective in numerous animal models of cardiovascular diseases ( 17 ). Controversially, several in vitro and animal investigations have raised concerns that linoleic acid and other n-6 PUFAs may induce inflammation and thrombosis ( 18 ).…”