Tolstik, E. | bioRxiv Science

bioRxiv2024

Enhanced cardiac mitochondrial biogenesis by nitro-oleic acid remedies diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction

Prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunctions contribute to HFpEF progression. Nitro-oleic acid (NO2-OA) impacts metabolic processes by improving glucose tolerance and adipocyte function. In this study, 4 week treatment with NO2-OA ameliorated diastolic dysfunction in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. A proteomic analysis of left ventricular tissue revealed, that one third of the identified proteins, mostly mitochondrial proteins, were upregulated in hearts of NO2-OA-treated HFpEF mice compared to controls and vehicle-treated HFpEF mice, which was confirmed by immunoblot. Activation of the 5-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediated an enhancement of mitochondrial biogenesis in hearts of NO2-OA-treated HFpEF mice. In cardiomyocytes under metabolic stress, NO2-OA increased mitochondrial protein level accompanied by enhanced oxidative phosphorylation. In conclusion, targeting mitochondrial integrity in HFpEF leads to improved diastolic function.

pathology↗

bioRxiv2023

Canonical and noncanonical contribution of thyroid hormone receptor isoforms alpha and beta to cardiac hypertrophy and heart rate in male mice

BackgroundStimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). Aim of this study was to determine in vivo which TH receptor (TR), or {beta}, and which mode of TR action, canonical gene expression or DNA-binding independent noncanonical action, mediate these effects. Material and methodsWe compared global TR and TR{beta} knockout mice (TRKO; TR{beta}KO) with WT mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA- binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRGS; TR{beta}GS). Hearts were studied with echocardiography at baseline and after seven weeks T3-treatment. Gene expression was measured with real-time PCR. Heart rate was recorded with radiotelemetry transmitters for seven weeks in untreated, hypothyroid and T3-treated mice. ResultsT3 induced ventricular hypertrophy in WT and TR{beta}KO mice, but not in TRKO mice. Hypertrophy was also induced in TRGS mice. Thus, hypertrophy is mostly mediated by noncanonical TR action. Similarly, repression of Mhy7 occurred in WT and TRGS mice. Basal heart rate was largely dependent on canonical TR action. But responsiveness to hypothyroidism and T3-treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRKO mice, demonstrating that TR{beta} could compensate for absence of TR. ConclusionT3-induced cardiac hypertrophy could be attributed to noncanonical TR action, whereas heart rate regulation was mediated by canonical TR action. TR{beta} could substitute for canonical, but not noncanonical TR action.

physiology↗