Targeting mitochondrial biogenesis restores diastolic dysfunction in heart failure with preserved ejection fraction

Marion Müller (Bad Oeynhausen)1, T. Schubert (Bad Oeynhausen)1, C. Welke (Bad Oeynhausen)1, T. Patschkowski (Bielefeld)2, T. Maske (Bad Oeynhausen)1, E. Donhauser (Bad Oeynhausen)3, V. Rudolph (Bad Oeynhausen)4, U. Schlomann (Bad Oeynhausen)1, A. Klinke (Bad Oeynhausen)4

1Herz- und Diabeteszentrum NRW Agnes Wittenborg Institut für translationale Herz-Kreislaufforschung Bad Oeynhausen, Deutschland; 2Universität Bielefeld Technology Platform Genomics, Center for Biotechnology (CeBiTec) Bielefeld, Deutschland; 3Herz- und Diabeteszentrum NRW Bad Oeynhausen, Deutschland; 4Herz- und Diabeteszentrum NRW Allgemeine und Interventionelle Kardiologie/Angiologie Bad Oeynhausen, Deutschland


Heart failure with preserved ejection fraction (HFpEF) is a disorder with heterogenous phenotypes derived from different pathophysiological mechanisms, which might require tailored therapies. Cardiometabolic HFpEF characterized by comorbidities such as obesity and diabetes mellitus is driven by alterations in cardiac metabolism and impaired energy supply. Nitro-oleic acid (NO2-OA) is an electrophilic molecule which has been identified to exert protective properties in various animal models. It is known to impact metabolic processes by improving glucose tolerance and adipocyte function. In this study, we sought to investigate the effects of NO2-OA on cardiac function in the ‘two-hit’ HFpEF mouse model mimicking cardiometabolic HFpEF.
Methods and Results:
HFpEF was induced by a combination of high fat diet (HFD) and endothelial NO synthase (eNOS) inhibition with Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) for 15 weeks in C57BL/6N mice. At week 11, mice received either NO2-OA (HFD+L-NAME NO2-OA; N=6) or vehicle (HFD+L-NAME; N=8) via mini-osmotic pumps for 4 weeks. Control (Ctrl) mice received a chow diet (N=9). As previously described, NO2-OA significantly lowered body weight (HFD+L-NAME NO2-OA: 38.6 ± 1.9 g; HFD+L-NAME: 42.4 ± 4.0 g) and blood glucose level (HFD+L-NAME NO2-OA: 163.8 ± 29.9 mg/dL; HFD+L-NAME: 239.2 ± 32.6 mg/dL). A proteome analysis of murine left ventricular (LV) tissue displayed altered lipid handling in HFD+L-NAME mouse hearts compared to controls. Treatment with NO2-OA normalized the cardiometabolic profile of HFD+L-NAME mice. Interestingly, 27% of all identified proteins (482 proteins out of 1796 proteins) were significantly increased in hearts of NO2-OA-treated HFD+L-NAME mice compared to vehicle-treated HFD+L-NAME mice (significance > -log10(0.05); difference > log2(1.5)). Annotation of the enriched proteins by NO2-OA in HFD+L-NAME mouse hearts identified mostly mitochondrial proteins located in the outer mitochondrial membrane (mitoCarta data base). KEGG-pathway analysis revealed significant changes in the protein level of proteins associated with the 5' adenosine monophosphate-activated protein kinase (AMPK) signaling pathway (p < 0.0001). Further immunoblot analysis confirmed significantly increased AMPK phosphorylation in NO2-OA treated HFD+L-NAME mouse hearts. In line, the protein level of the NAD dependent deacetylates sirtuin 1 and sirtuin 3 were enhanced by NO2-OA treatment, resulting in increased mitochondrial biogenesis as reflected by significantly increased mitochondrial copy number after NO2-OA treatment in HFD+L-NAME mouse hearts. Remarkable, diastolic dysfunction was ameliorated after treatment with NO2-OA in HFD+L-NAME mice measured by echocardiography (E/e’: HFD+L-NAME NO2-OA: 34.3 ± 13.3; HFD+L-NAME: 68.4 ± 31.3). Treatment of HFD+L-NAME mice with oleic acid (OA) had no significant effect on cardiac function, underlining the relevance of the nitro group.
Treatment of NO2-OA mediates sirtuin expression via activation of the AMPK signaling pathway leading to enhanced mitochondrial biogenesis in HFpEF mouse hearts. Thus, targeting mitochondrial biogenesis in HFpEF contributes to a beneficial cardiometabolic protein profile associated with improved diastolic function. 
Diese Seite teilen