Anti-arrhythmic and anti-fibrotic effects of nitrated fatty acids in myocardial remodeling.
Final Report Abstract
Endogenously formed nitrated fatty acids (NO2-FA) had been identified before to exert antiinflammatory and anti-oxidative properties. Nitro-oleic acid (NO2-OA) and nitro-linoleic acid (NO2-LA) had been synthetized and administered in murine models and in phase I and II clinical studies during the past 15 years. It was observed that these molecules react with nucleophiles thereby modifying the function of a variety of proteins, which induced protective effects in different disease models. With this project we aimed to expand our understanding of the properties and therapeutic potential of NO2-OA and investigate its effects in murine models of cardiovascular diseases. In particular, we proposed to characterize anti-arrhythmic effects in the early phase of myocardial infarction in mice and to characterize anti-fibrotic and antiinflammatory effects in murine heart failure. We applied NO2-OA to mice during myocardial ischemia and tested for anti-arrhythmic effects by an electrophysiological investigation, which revealed that the susceptibility to ventricular tachycardia was markedly reduced by NO2-OA. In line with that, electrical inhomogeneity derived from electrophysiological mapping analyses was significantly alleviated. We found out, that isoproterenol-induced activation of calcium/calmodulin dependent protein kinase II (CaMKII) and subsequent phosphorylation of ryanodine receptor 2 was diminished by NO2-OA in isolated cardiomyocytes. To address the anti-fibrotic actions of NO2-OA, we administered it to mice deficient of the sarcomeric muscle LIM protein MLP. These mice develop a dilated cardiomyopathy with prominent interstitial fibrosis. NO2-OA improved left ventricular (LV) systolic function in these mice in part via reduction of fibrotic remodelling mediated by transforming growth factor β (TGFβ). Given that the development of aortic aneurysm in Marfan syndrome (MFS) is also importantly mediated by TGFβ, we then investigated whether NO2-OA might have an effect in Fbn1C1039G/+ mice (MFS mice), which develop MFS due to a mutation in the fibrillin 1 gene. Indeed, NO2-OA significantly reduced aneurysm formation in MFS mice and in MFS mice treated with angiotensin II, where it profoundly increased survival of the mice. The effects where related in part to reduced activity of matrix metalloproteinases 2 and 9 in aortic tissue by NO2-OA and subsequent attenuation of elastin strand breaks. Apart from novel therapeutic approaches for left heart diseases, we sought to address dysfunction and failure of the right heart, which is less understood and lacks therapeutic options. We found out that the development of right heart failure in mice upon pressure overload was in part prevented by therapeutic or genetic reduction of mitochondrial reactive oxygen species. Therefor we currently investigate the effects of NO2-OA on RHF in this mouse model. Finally, we aimed to test whether NO2-OA might also be effective to treat heart failure with preserved ejection fraction (HFpEF). We used the mouse model of high fat diet (HFD) feeding and inhibition of the endothelial nitric oxide synthase (eNOS) with L-NAME and observed, that blood glucose levels where normalized by NO2-OA and diastolic dysfunction was alleviated. In NO2-OA-treated mice we found a reduction of oxidative stress in the LV compared to vehicle-treated mice, which might contribute to the improvement of diastolic function and is a matter of current analyses. In summary, our experiments impressively showed that NO2-OA exhibits a broad preventive and therapeutic potential in left heart and vascular diseases in mice. We will continue to characterize the potential application and the mechanisms of action in cardiovascular diseases, to deepen the understanding of this promising molecule and to support its development as a novel drug.
Publications
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Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis. Sci Rep. 2020 Sep 18;10(1):15319
Mollenhauer M, Mehrkens D, Klinke A, Lange M, Remane L, Friedrichs K, Braumann S, Geißen S, Simsekyilmaz S, Nettersheim FS, Lee S, Peinkofer G, Geisler AC, Geis B, Schwoerer AP, Carrier L, Freeman BA, Dewenter M, Luo X, El-Armouche A, Wagner M, Adam M, Baldus S, Rudolph V
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Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis. Int J Mol Sci. 2021 Aug 22;22(16):9052
Braumann S, Schumacher W, Im NG, Nettersheim FS, Mehrkens D, Bokredenghel S, Hof A, Nies RJ, Adler C, Winkels H, Knöll R, Freeman BA, Rudolph V, Klinke A, Adam M, Baldus S, Mollenhauer M, Geißen S
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Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome. Cardiovasc Res. 2022 Jul 20;118(9):2211-2225
Nettersheim FS, Lemties J, Braumann S, Geißen S, Bokredenghel S, Nies R, Hof A, Winkels H, Freeman BA, Klinke A, Rudolph V, Baldus S, Mehrkens D, Mollenhauer M, Adam M
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Right Heart Failure in Mice Upon Pressure Overload Is Promoted by Mitochondrial Oxidative Stress. JACC Basic Transl Sci. 2022 Jul 6;7(7):658-677
Müller M, Bischof C, Kapries T, Wollnitza S, Liechty C, Geißen S, Schubert T, Opacic D, Gerçek M, Fortmeier V, Dumitrescu D, Schlomann U, Sydykov A, Petrovic A, Gnatzy-Feik L, Milting H, Schermuly RT, Friedrichs K, Rudolph V, Klinke A
