The BET bromodomain inhibitor I-BET-151 induces structural and functional alterations of the heart mitochondria in healthy male mice and rats

The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications

Cardioprotective reperfusion strategies differentially affect mitochondria:studies in an isolated rat heart model of donation after circulatory death (DCD).

Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability, however concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of pre-ischemic treatments is limited for ethical reasons, thus cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia-reperfusion injury, we hypothesize that three reperfusion strategies: mild hypothermia, mechanical post-conditioning and hypoxia, when briefly applied at reperfusion onset, provoke mitochondrial changes that may underlie their cardioprotective effects. Using an isolated, working rat heart model of DCD, we demonstrate that all three strategies improve oxygen-consumption-cardiac-work coupling and increase tissue ATP content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical post-conditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia up-regulates the expression of Pgc-1α (regulator of mitochondrial biogenesis). Characterisation of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochochondrial-based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation. This article is protected by copyright. All rights reserved

Cardioprotective reperfusion strategies differentially affect mitochondria: Studies in an isolated rat heart model of donation after circulatory death (DCD)

International audienceDonation after circulatory death (DCD) holds great promise for improving cardiac graft availability; however, concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of preischemic treatments is limited for ethical reasons; thus, cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia-reperfusion injury, we hypothesize that 3 reperfusion strategies-mild hypothermia, mechanical postconditioning, and hypoxia, when briefly applied at reperfusion onset-provoke mitochondrial changes that may underlie their cardioprotective effects. Using an isolated, working rat heart model of DCD, we demonstrate that all 3 strategies improve oxygen-consumption-cardiac-work coupling and increase tissue adenosine triphosphate content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical postconditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia upregulates the expression of peroxisome proliferator-activated receptor-gamma coactivator (regulator of mitochondrial biogenesis). Characterization of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochondrial-based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation

SIRT1 protects the heart from ER stress-induced cell death through eIF2α deacetylation

Over the past decade, endoplasmic reticulum (ER) stress has emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. Cardiac therapy based on ER stress modulation is viewed as a promising avenue toward effective therapies for the diseased heart. Here, we tested whether sirtuin-1 (SIRT1), a NAD(+)-dependent deacetylase, participates in modulating ER stress response in the heart. Using cardiomyocytes and adult-inducible SIRT1 knockout mice, we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury, whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective. Analysis of the expression of markers of the three main branches of the unfolded protein response (i.e., PERK/eIF2α, ATF6 and IRE1) showed that SIRT1 protects cardiomyocytes from ER stress-induced apoptosis by attenuating PERK/eIF2α pathway activation. We also present evidence that SIRT1 physically interacts with and deacetylates eIF2α. Mass spectrometry analysis identified lysines K141 and K143 as the acetylation sites on eIF2α targeted by SIRT1. Furthermore, mutation of K143 to arginine to mimic eIF2α deacetylation confers protection against ER stress-induced apoptosis. Collectively, our findings indicate that eIF2α deacetylation on lysine K143 by SIRT1 is a novel regulatory mechanism for protecting cardiac cells from ER stress and suggest that activation of SIRT1 has potential as a therapeutic approach to protect the heart against ER stress-induced injury