Universität zu Köln

Braumann, Simon, Schumacher, Wibke ORCID: 0000-0003-0277-8070, Im, Nam Gyu, Nettersheim, Felix Sebastian, Mehrkens, Dennis ORCID: 0000-0002-8578-0290, Bokredenghel, Senai, Hof, Alexander ORCID: 0000-0001-6554-8892, Nies, Richard Julius, Adler, Christoph, Winkels, Holger, Knoell, Ralph, Freeman, Bruce A., Rudolph, Volker, Klinke, Anna, Adam, Matti, Baldus, Stephan, Mollenhauer, Martin and Geissen, Simon (2021). Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis. Int. J. Mol. Sci., 22 (16). BASEL: MDPI. ISSN 1422-0067

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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 TGF beta 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 TGF beta-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 TGF beta 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 TGF beta signaling.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Braumann, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, Wibke UNSPECIFIED orcid.org/0000-0003-0277-8070 UNSPECIFIED Im, Nam Gyu UNSPECIFIED UNSPECIFIED UNSPECIFIED Nettersheim, Felix Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Mehrkens, Dennis UNSPECIFIED orcid.org/0000-0002-8578-0290 UNSPECIFIED Bokredenghel, Senai UNSPECIFIED UNSPECIFIED UNSPECIFIED Hof, Alexander UNSPECIFIED orcid.org/0000-0001-6554-8892 UNSPECIFIED Nies, Richard Julius UNSPECIFIED UNSPECIFIED UNSPECIFIED Adler, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Winkels, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Knoell, Ralph UNSPECIFIED UNSPECIFIED UNSPECIFIED Freeman, Bruce A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rudolph, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED Klinke, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Adam, Matti UNSPECIFIED UNSPECIFIED UNSPECIFIED Baldus, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mollenhauer, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Geissen, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-590552
DOI:	10.3390/ijms22169052
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	22
Number:	16
Date:	2021
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TGF-BETA; FATTY-ACIDS; CARDIAC FIBROSIS; MURINE MODEL; PATHWAYS; OUTCOMES; STAT3 Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59055