MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload

Michael P Murphy,Peter A Hecker,Erinne Rose Dabkowski,Rogério Faustino Ribeiro Junior,Kelly A O´Connell,Kadambari Chandra Shekar

doi:10.1016/j.freeradbiomed.2018.01.012

Abstract

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.

Highlights

Despite diagnosis and treatment, heart failure remains a major clinical problem and a huge economic burden on the health care system
MitoQ decreased right ventricular hypertrophy and lung congestion induced by pressure overload after 14 weeks
TAC animals did not present ejection fraction below 30–40% which is the main criteria for heart failure classification, the animals present Lung/BW ≥ Lung/BWSham; + 2 SD (Lung wet weight; BW = body weight; SD = standard deviation); RV hypertrophy was proportional to Lung/BW (Tables 1 and 2) [26,28]

Summary

Introduction

Heart failure remains a major clinical problem and a huge economic burden on the health care system. The disease is highly prevalent in elderly patients and is associated with high mortality rates within five years of diagnosis despite current optimal medical therapy. Current medical therapy can prevent new onset and slow the progression once heart failure is established but prognosis is still poor even for most favorable treated patients, and new therapeutic approaches are needed. Heart failure rehospitalizations rates remain high (35%) within 90 days after discharge and this event has not changed over the last 15 years [1,2,3,4,5]. Prescribed therapies beneficial in improving some symptoms often do not approach the underlying causes of progressive left ventricular dysfunction presented in heart failure [6]

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