Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D

Bochaton, Thomas; Crola-da-Silva, Claire; Pillot, Bruno; Villedieu, Camille; Ferreras, Laura; Alam, Muhammad Rizwan; Thibault, Hélène; Strina, M.; Gharib, Abdallah; Ovize, Michel; Baetz, Delphine

doi:10.1016/j.yjmcc.2015.03.017

Cited by 100 publications

(101 citation statements)

References 39 publications

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“…As mentioned above, SIRT3 is able to deacetylate the mPTP component CyPD and inhibit its opening. Bochaton et al (2015) confirmed that SIRT3 was also necessary for the prevention of reperfusion injury via a mechanism which is similar to that observed with the inhibition of mPTP opening by CyPD. Thus, while SIRT3 plays an important role in protecting cardiomyocytes from oxidative or ischemia reperfusion injury in vitro, it remains to be determined if the same effects can be seen in vivo.…”

Section: Role Of Sirt3 In Attenuating Ischemia And/or Reperfusion-indsupporting

confidence: 79%

Roles of SIRT3 in heart failure: from bench to bedside

Liu

Song

et al. 2016

J. Zhejiang Univ. Sci. B

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Heart failure (HF) represents the most common endpoint of most cardiovascular diseases (CVDs) which are the leading causes of death around the world. Despite the advances in treating CVDs, the prevalence of HF continues to increase. It is believed that better results of prognosis are obtained from prevention rather than additional treatment for HF. Therefore, it is reasonable to prevent the development of CVDs or other complications to HF. Most types of HF are attributed to contractile dysfunction, cardiac hypertrophy or remodeling, and ischemic injuries. SIRT3 is a mitochondrial nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase whose substrates vary from metabolic biogenesis-associated proteins to stress-responsive proteins. In recent years, a number of studies have highlighted the cardio-protective role of SIRT3 and, as such, efforts have been made to induce over-expression or increased activity of this protein. In this review, we provide an overview of the roles of SIRT3 in cardiac hypertrophy induced by pressure overload or agonists and cardiomyocytes ischemic injuries. Moreover, we will introduce the application of SIRT3 agonists in the prevention of cardiac hypertrophy and ischemia reperfusion injury.

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Section: Role Of Sirt3 In Attenuating Ischemia And/or Reperfusion-indsupporting

confidence: 79%

Roles of SIRT3 in heart failure: from bench to bedside

Liu

Song

et al. 2016

J. Zhejiang Univ. Sci. B

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“…In two of these solutions, OSCP-K70 was in close proximity (3.1 Å) of CypD-K66 which would result in charge repulsion, destabilizing the OSCP-CypD interaction (Figure 7A right panel, magenta sticks). Previous studies suggest that hyperacetylation of CypD-K166 modulate mPTP sensitivity 31, 32 . Although CypD-K166Ac was not detected in our acetylome analysis (Table S5), it was one of the lysines from CypD found within the interaction interface out of the highest scoring docking solutions.…”

Section: Resultsmentioning

confidence: 93%

Normalization of NAD ⁺ Redox Balance as a Therapy for Heart Failure

et al. 2016

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Background heart failure has become increasingly prevalent along with the aging population and the increased survival of acute ischemic heart events. Impairments of mitochondrial function in the heart are intricately linked to the development of heart failure but there is no therapy for mitochondrial dysfunction in the clinic. Methods and Results we report that NAD+ redox imbalance (increased NADH/NAD+) and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, are also present in human failing hearts as well as in mouse hearts with pathological hypertrophy. Elevation of NAD+ levels by stimulating the NAD+ salvage pathway suppressed mitochondrial protein hyperacetylation and cardiac hypertrophy, and improved cardiac function in responses to stresses. Acetylome analysis identified a subpopulation of mitochondrial proteins that was sensitive to changes in the NADH/NAD+ ratio. Hyperacetylation of mitochondrial malate-aspartate shuttle proteins impaired the transport and oxidation of cytosolic NADH in the mitochondria, resulting in altered cytosolic redox state and energy deficiency. Furthermore, acetylation of oligomycin-sensitive conferring protein at lysine-70 in ATP synthase complex promoted its interaction with cyclophilin D, and sensitized the opening of mitochondrial permeability transition pore. Both could be alleviated by normalizing the NAD+ redox balance either genetically or pharmacologically. Conclusions we show that mitochondrial protein hyperacetylation due to NAD+ redox imbalance contributes to the pathological remodeling of the heart via two distinct mechanisms. Our preclinical data demonstrate a clear benefit of normalizing NADH/NAD+ imbalance in the failing hearts. These findings have a high translational potential as the pharmacological strategy of increasing NAD+ precursors are feasible in human.

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“…Acetylation is a very important regulator of enzymatic function and protein-protein interaction in the mitochondria [1,4,44]. Other studies have demonstrated a potential role for mitochondrial protein acetylation in the response to I/R injury, with most studies focusing on the effects of SIRT3-mediated acetylation in I/R [45,46]. Interestingly, recent work utilizing a Cyclophilin D knockout, a model that is resistant to ischemia-reperfusion injury [47], demonstrated increased acetylation of mitochondrial proteins [48].…”

Section: Discussionmentioning

confidence: 99%

HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury

Herr

Baarine

Aune

et al. 2018

Journal of Molecular and Cellular Cardiology

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Rationale Recent evidence indicates that histone deacetylase enzymes (HDACs) contribute to ischemia re-perfusion (I/R) injury, and pan-HDAC inhibitors have been shown to be cardioprotective when administered either before an ischemic insult or during reperfusion. We have shown previously that selective inhibition of class I HDACs provides superior cardioprotection when compared to pan-HDAC inhibition in a pretreatment model, but selective class I HDAC inhibition has not been tested during reperfusion, and specific targets of class I HDACs in I/R injury have not been identified. Objective We hypothesized that selective inhibition of class I HDACs with the drug MS-275 (entinostat) during reperfusion would improve recovery from I/R injury in the first hour of reperfusion. Methods and results Hearts from male Sprague-Dawley rats were subjected to ex vivo I/R injury ± MS-275 class I HDAC inhibition during reperfusion alone. MS-275 significantly attenuated I/R injury, as indicated by improved LV function and tissue viability at the end of reperfusion. Unexpectedly, we observed that HDAC1 is present in the mitochondria of cardiac myocytes, but not fibroblasts or endothelial cells. We then designed mitochondria-restricted and mitochondria-excluded HDAC inhibitors, and tested both in our ex vivo I/R model. The selective inhibition of mitochondrial HDAC1 attenuated I/R injury to the same extent as MS-275, whereas the mitochondrial-excluded inhibitor did not. Further assays demonstrated that these effects are attributable to a decrease in SDHA activity and subsequent metabolic ROS production in reperfusion. Conclusions We demonstrate for the first time that HDAC1 is present within the mitochondria of cardiac myocytes, and mitochondrial HDAC1 contributes significantly to I/R injury within the first hour of reperfusion.

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Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D

Cited by 100 publications

References 39 publications

Roles of SIRT3 in heart failure: from bench to bedside

Roles of SIRT3 in heart failure: from bench to bedside

Normalization of NAD ⁺ Redox Balance as a Therapy for Heart Failure

HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury

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Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D

Cited by 100 publications

References 39 publications

Roles of SIRT3 in heart failure: from bench to bedside

Roles of SIRT3 in heart failure: from bench to bedside

Normalization of NAD + Redox Balance as a Therapy for Heart Failure

HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury

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Normalization of NAD ⁺ Redox Balance as a Therapy for Heart Failure