mitoquinone and Heart-Failure

The current therapy for patients with stable systolic heart failure is largely limited to treatments that interfere with neurohormonal activation. Critical pathophysiological hallmarks of heart failure are an energetic deficit and oxidative stress, and both may be the result of mitochondrial dysfunction. This dysfunction is not (only) the result of defect within mitochondria per se, but is in particular traced to defects in intermediary metabolism and of the regulatory interplay between excitation-contraction coupling and mitochondrial energetics, where defects of cytosolic calcium and sodium handling in failing hearts may play important roles. In the past years, several therapies targeting mitochondria have emerged with promising results in preclinical models. Here, we discuss the mechanisms and results of these mitochondria-targeted therapies, but also of interventions that were not primarily thought to target mitochondria but may have important impact on mitochondrial biology as well, such as iron and exercise. Future research should be directed at further delineating the details of mitochondrial dysfunction in patients with heart failure to further optimize these treatments.

Topics: Antioxidants; Dietary Supplements; Exercise Therapy; Heart Failure; Humans; Iron; Mitochondria, Heart; Oligopeptides; Organophosphorus Compounds; Trace Elements; Ubiquinone; Vitamins

Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day

Topics: Animals; Antioxidants; Disease Models, Animal; Heart Failure; Mice; Mitochondria; Mitochondrial Dynamics; Myocardium; Myocytes, Cardiac; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; RNA, Untranslated; Ubiquinone

Increasing evidence indicates that mitochondrial-associated redox signaling contributes to the pathophysiology of heart failure (HF). The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is capable of modifying mitochondrial signaling and has shown beneficial effects on HF-dependent mitochondrial dysfunction. However, the potential therapeutic impact of MitoQ-based mitochondrial therapies for HF in response to pressure overload is reliant upon demonstration of improved cardiac contractile function and suppression of deleterious cardiac remodeling. Using a new (patho)physiologically relevant model of pressure overload-induced HF we tested the hypothesis that MitoQ is capable of ameliorating cardiac contractile dysfunction and suppressing fibrosis. To test this C57BL/6J mice were subjected to left ventricular (LV) pressure overload by ascending aortic constriction (AAC) followed by MitoQ treatment (2 µmol) for 7 consecutive days. Doppler echocardiography showed that AAC caused severe LV dysfunction and hypertrophic remodeling. MitoQ attenuated pressure overload-induced apoptosis, hypertrophic remodeling, fibrosis and LV dysfunction. Profibrogenic transforming growth factor-β1 (TGF-β1) and NADPH oxidase 4 (NOX4, a major modulator of fibrosis related redox signaling) expression increased markedly after AAC. MitoQ blunted TGF-β1 and NOX4 upregulation and the downstream ACC-dependent fibrotic gene expressions. In addition, MitoQ prevented Nrf2 downregulation and activation of TGF-β1-mediated profibrogenic signaling in cardiac fibroblasts (CF). Finally, MitoQ ameliorated the dysregulation of cardiac remodeling-associated long noncoding RNAs (lncRNAs) in AAC myocardium, phenylephrine-treated cardiomyocytes, and TGF-β1-treated CF. The present study demonstrates for the first time that MitoQ improves cardiac hypertrophic remodeling, fibrosis, LV dysfunction and dysregulation of lncRNAs in pressure overload hearts, by inhibiting the interplay between TGF-β1 and mitochondrial associated redox signaling.

Topics: Animals; Apoptosis; Biomarkers; Cardiomegaly; Disease Models, Animal; Echocardiography; Fibroblasts; Fibrosis; Heart Failure; Immunohistochemistry; Male; Mice; Models, Biological; Myocardium; Organophosphorus Compounds; Signal Transduction; Stress, Mechanical; Transforming Growth Factor beta; Ubiquinone; Ventricular Dysfunction, Left; Ventricular Remodeling

Heart failure remains a major public-health problem with an increase in the number of patients worsening from this disease. Despite current medical therapy, the condition still has a poor prognosis. Heart failure is complex but mitochondrial dysfunction seems to be an important target to improve cardiac function directly. Our goal was to analyze the effects of MitoQ (100 µM in drinking water) on the development and progression of heart failure induced by pressure overload after 14 weeks. The main findings are that pressure overload-induced heart failure in rats decreased cardiac function in vivo that was not altered by MitoQ. However, we observed a reduction in right ventricular hypertrophy and lung congestion in heart failure animals treated with MitoQ. Heart failure also decreased total mitochondrial protein content, mitochondrial membrane potential in the intermyofibrillar mitochondria. MitoQ restored membrane potential in IFM but did not restore mitochondrial protein content. These alterations are associated with the impairment of basal and stimulated mitochondrial respiration in IFM and SSM induced by heart failure. Moreover, MitoQ restored mitochondrial respiration in heart failure induced by pressure overload. We also detected higher levels of hydrogen peroxide production in heart failure and MitoQ restored the increase in ROS production. MitoQ was also able to improve mitochondrial calcium retention capacity, mainly in the SSM whereas in the IFM we observed a small alteration. In summary, MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload, by decreasing hydrogen peroxide formation, improving mitochondrial respiration and improving mPTP opening.

Topics: Animals; Antioxidants; Disease Models, Animal; Heart Failure; Mitochondria; Mitochondria, Heart; Organophosphorus Compounds; Rats; Ubiquinone