Heme oxygenase-1 regulates mitochondrial quality control in the heart

Abstract

The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. It also prevented dynamic changes in the levels of key mediators of the mitophagy pathway, PINK1 and parkin. Therefore, these findings suggest that HO-1 has a novel role in protecting the heart from oxidative injury by regulating mitochondrial quality control.

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

“…HO‐1 catalyzes heme degradation to produce equimolar amounts of carbon monoxide (CO), which exhibits anti‐inflammatory properties, and biliverdin which is converted to bilirubin, a powerful antioxidant, by biliverdin reductase. In addition, HO‐1 and CO induce mitochondrial biogenesis (Piantadosi et al, 2011) and recent findings indicate that this system is also implicated in mitochondrial quality control (Hull et al, 2016). The expression of HO‐1 is induced in smokers with mild COPD as compared to smoker controls (Maestrelli et al, 2001), revealing a potential protective role of this enzyme against oxidative stress‐mediated cell senescence and mitochondrial dysfunction in COPD.…”

Mitochondrial quality-control dysregulation in conditional HO-1–/– mice

“…The induction of HO-1 leads to increased cellular CO production, which generates a redox signal for the induction of mitochondrial biogenesis through stimulation of mitochondrial ROS production (5,23). HO-1 has also been implicated in the induction of macroautophagy, (24) and if this capacity includes mitophagy, the enzyme would be involved in the regulation of the entire mitochondrial quality control cycle, which enables accurate and precise mitochondrial turnover (24)(25)(26). Disruption of mitophagy is proinflammatory and prooxidant (27,28), and impaired autophagy compromises bioenergetics and leads to cell death, chronic inflammatory heart disease, and HF progression (29,30).…”

Cardioproductive Effects of Exxenate Amid and Vildagliptin Incretin Mimetics in Doxyrubricine Cardiomyopathy Modeling

“…Точные механизмы, лежащие в основе влияния ГПП-1 на сердечную мышцу, до сих пор не установлены [7,8,9]. Предполагается, что ГПП-1 может положительно влиять на апоптоз кардиомиоцитов, окислительный стресс и эндо-генные антиоксидантные защитные механизмы, при этом оказывая благоприятное воздействие в отношении кардиопротекции миокарда [10,11,6,12].…”

“…Активация гем-оксигеназы-1 ассоциирована с усилением катаболизма гема до желчных пигментов, явля-ющихся потенциальными эндогенными антиокси-дантами. Кроме того, индукция гем-оксигеназы-1 сопровождается увеличением активности фер-ритина, что оказывает антиапоптотический эф-фект [10]. Усиление экспрессии гем-оксигеназы-1 в условиях оксидативного стресса может играть адаптивную роль в ответ на оксидативное по-вреждение и уменьшать гибель кардиомиоцитов.…”

“…Это, также, предотвращает мутации в ключевых генах митохондрий PINK1 и PARKIN и обеспечивает их нормальную работу. Это до-казывает, что НО-1 играет немаловажную роль в защите сердца от окислительного повреждения оказывая влияние на митохондрии [10,23]. В свя-зи с вышеизложенным, можно предположить, что в механизме защитного действия инкритиноми-метиков при доксорубициновой миокардиопатии принимают участие механизмы экспрессии анти-оксидантной защиты.…”