Selective inhibition of class I but not class IIb histone deacetylases exerts cardiac protection from ischemia reperfusion

Aune, Sverre E.; Herr, D.; Mani, Santhosh K.; Menick, Donald R.

doi:10.1016/j.yjmcc.2014.03.005

Cited by 79 publications

(64 citation statements)

References 39 publications

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“…Although PCI and angioplasty limit ischemic injury, reperfusion itself injures the heart by increasing ROS. We and others have shown that HDAC inhibition preceding ischemia reperfusion (I/R) injury in the heart can preserve left ventricular function and myocardial survival [29–31]. Importantly, we demonstrated that the selective inhibition of class I HDACs was more effective than pan-HDAC inhibition in preserving myocardial viability and function in the setting of I/R injury.…”

Section: Introductionmentioning

confidence: 65%

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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Section: Introductionmentioning

confidence: 65%

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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“…More than one study has demonstrated a significant decrease in infarct size and myocardial cell death with class I/IIb HDAC inhibitor treatment (18,60). We recently demonstrated that class I HDAC inhibition conferred protective benefits to the ischemic reperfused heart and that inhibition of HDAC6, a class IIb HDAC, provided no beneficial effects (3).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction

Mani

Kern

Kimbrough

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb-and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI. myocardial infarction; histone deacetylase; matrix metalloproteinases; transcriptional regulation; macrophages; LV remodeling THE HEALING RESPONSE within the myocardium after a myocardial infarction (MI) is complex and involves both temporal and regional changes, including inflammation, new tissue formation, and tissue remodeling (11). After coronary artery occlusion, there is an induction of bioactive peptides and cytokines, extracellular matrix (ECM) degradation, and subsequent recruitment of inflammatory cells to the site of injury (9,16,53). Alterations in the post-MI ECM architecture are largely attributed to changes in the expression of a number of matrix metalloproteases (MMPs) (50). Previous work has demonstrated that induction of MMP-2 gene expression can be detected by day 1 post-MI, reaches its maximum at 7 days, and then gradually decreases (43, 51). Activation of the MMP-9 promoter was detectable by 3 days, peaked by 7 days, and remained upregulated throughout the 28-day time course post-MI (43). The dramatic increases in both MMP-2 and MMP-9 have been proposed to contribute to the disruption of the cardiocyte-matrix interactive network, resulting in cardiocyte misalignment and slippage (53).MMP-9-null mice show attenuated left ventricular (LV) dilation and improved LV function compared w...

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“…As described previously 7 , this pressure trace can be used to calculate many of the parameters of ventricular function. These calculations can be made in the baseline phase as well as the reperfusion phase, averaged over multiple traces within each group, and compared in order to determine whether the pharmacological intervention resulted in cardiac preconditioning, as we have done previously 9 . One such parameter is the developed pressure, calculated as the difference between the systolic pressure and the end diastolic pressure.…”

Section: Representative Resultsmentioning

confidence: 99%

“…The isolated perfused rat heart can be successfully used to study the effect of pharmacological intervention on cardiac preconditioning in ischemia reperfusion injury 9 . However, there are some essential steps to the procedure that must be standardized in order to ensure reproducible results.…”

Section: Discussionmentioning

confidence: 99%

Induction and Assessment of Ischemia-reperfusion Injury in Langendorff-perfused Rat Hearts

Herr

Aune

Menick

2015

JoVE

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The biochemical events surrounding ischemia reperfusion injury in the acute setting are of great importance to furthering novel treatment options for myocardial infarction and cardiac complications of thoracic surgery. The ability of certain drugs to precondition the myocardium against ischemia reperfusion injury has led to multiple clinical trials, with little success. The isolated heart model allows acute observation of the functional effects of ischemia reperfusion injury in real time, including the effects of various pharmacological interventions administered at any time-point before or within the ischemia-reperfusion injury window. Since brief periods of ischemia can precondition the heart against ischemic injury, in situ aortic cannulation is performed to allow for functional assessment of non-preconditioned myocardium. A saline filled balloon is placed into the left ventricle to allow for real-time measurement of pressure generation. Ischemic injury is simulated by the cessation of perfusion buffer flow, followed by reperfusion. The duration of both ischemia and reperfusion can be modulated to examine biochemical events at any given time-point. Although the Langendorff isolated heart model does not allow for the consideration of systemic events affecting ischemia and reperfusion, it is an excellent model for the examination of acute functional and biochemical events within the window of ischemia reperfusion injury as well as the effect of pharmacological intervention on cardiac pre-and postconditioning. The goal of this protocol is to demonstrate how to perform in situ aortic cannulation and heart excision followed by ischemia/reperfusion injury in the Langendorff model. Video LinkThe video component of this article can be found at

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Selective inhibition of class I but not class IIb histone deacetylases exerts cardiac protection from ischemia reperfusion

Cited by 79 publications

References 39 publications

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

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

Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction

Induction and Assessment of Ischemia-reperfusion Injury in Langendorff-perfused Rat Hearts

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