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

Simon Braumann,Nam Gyu Im,Bruce A Freeman,Simon Geißen,Alexander Hof,Dennis Mehrkens,Senai Bokredenghel,Ralph Knöll,Christoph Adler,Felix Sebastian Nettersheim,Holger Winkels,Richard Julius Nies,Wibke Schumacher,Martin Mollenhauer,Stephan Baldus,Volker Rudolph,Anna Klinke,Matti Adam

doi:10.3390/ijms22169052

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.

Highlights

Dilated cardiomyopathy (DCM) is a major health issue in Western countries with high incidence and mortality rate and the most frequent cause for heart transplantation [1,2]
We investigated the effects of Nitro-oleic acid (NO2-OA) on dilated cardiomyopasignificantly improves left ventricular systolic function; (ii) the extensive myocardial fibrothy in Mlp−/− mice
We show for the first time that: (i) treatment with NO2-OA significantly sis in Mlp−/ − mice is attenuated by NO2 -OA; (iii) Transforming growth factor-β (TGFβ) signaling is increased in Mlp−/ −

Summary

Introduction

Dilated cardiomyopathy (DCM) is a major health issue in Western countries with high incidence and mortality rate and the most frequent cause for heart transplantation [1,2]. Ischemic heart disease is the most common cause for DCM, while up to 40% of non-ischemic. DCM are caused by genetic mutations [3]. Pathognomonic features of DCM are progressive dilation and systolic dysfunction of one or both ventricles, increased myocyte apoptosis and myocardial fibrosis [4,5,6]. Transforming growth factor-β (TGFβ) is a primary stimulus of fibrosis [7], via both canonical and non-canonical signaling pathways. While anti-fibrotic drug strategies sometimes blunt the progression of idiopathic pulmonary fibrosis and angiotensin-converting enzyme inhibitors have been shown to attenuate cardiac fibrosis, no specific anti-fibrotic agent is approved for DCM treatment [11,12,13]. One emerging group of anti-fibrotic therapeutics is nitrated fatty acids (NO2 -FA) [14]

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Results

Conclusion