Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 16, Pages -Publisher
MDPI
DOI: 10.3390/ijms22169052
Keywords
nitro-oleic acid; dilated cardiomyopathy; muscle LIM protein; myocardial fibrosis; TGF beta; alpha smooth muscle actin
Funding
- Deutsche Forschungsgemeinschaft [GRK 2407 (360043781), SFB TRR259 (397484323), RU1678/3-3, MO 3438/2-1]
- Center for Molecular Medicine Cologne [Baldus B-02]
- Koeln Fortune Program [344/2019, 363/2020]
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The study demonstrates a substantial therapeutic benefit of NO2-OA in a murine model of dilated cardiomyopathy, mediated by interfering with endogenously activated TGF beta signaling, that can attenuate myocardial fibrosis and substantially improve systolic function in the left ventricle.
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.
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