Inhibition of Histone Deacetylase Protects the Retina from Ischemic Injury

Crosson, Craig E.; Mani, Santhosh K.; Husain, Shahid; Alsarraf, Oday; Menick, Donald R.

doi:10.1167/iovs.09-4538

Cited by 88 publications

(73 citation statements)

References 41 publications

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“…On the other hand, HDACs could affect MMP-2 and MMP-9 expression indirectly, possibly by regulating the levels of inflammatory cytokines expressed and released in the infarct and border zones. We have shown that TSA treatment represses the induction of retinal TNF-␣ levels in rats subjected to retinal ischemia (13). Another study (24) has shown that long-term treatment with SAHA reduced circulating levels of multiple inflammatory cytokines, including TNF-␣, IL-1␤, and IL-6, in the rat DOCA-salt model of hypertensive cardiomyopathy.…”

Section: Discussionmentioning

confidence: 71%

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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Section: Discussionmentioning

confidence: 71%

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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“…This review includes a short overview of genetic associations between HDACs and the etiology of diabetes followed by a discussion of the potential for HDACi as an oral therapy with respect to modulation of the immune system, insulin resistance, β-cell development, differentiation and function, and pathogenetic events relevant for β-cell failure and destruction and islet graft rejection. Of note, HDACi also hold promise with respect to treatment of late diabetic complications such as diabetic nephropathy (28,29) and retinal ischemia playing a central role in diabetic retinopathy (30). HDACi and late diabetic complications will not be discussed further here, and readers are referred to the aforementioned references.…”

Section: Antiinflammatory Properties Of Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus

Christensen

Dahllöf

Lundh

et al. 2011

Mol Med

222

167

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Both common forms of diabetes have an inflammatory pathogenesis in which immune and metabolic factors converge on interleukin-1β as a key mediator of insulin resistance and β-cell failure. In addition to improving insulin resistance and preventing β-cell inflammatory damage, there is evidence of genetic association between diabetes and histone deacetylases (HDACs); and HDAC inhibitors (HDACi) promote β-cell development, proliferation, differentiation and function and positively affect late diabetic microvascular complications. Here we review this evidence and propose that there is a strong rationale for preclinical studies and clinical trials with the aim of testing the utility of HDACi as a novel therapy for diabetes.

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“…23 Briefly, we photographed 3 standard rectangular areas (0.2 · 0.2 mm; 0.04 mm 2 ) at 1, 2, and 3 mm, respectively, from the optic disc in the central region of each retinal quadrant (superotemporal, inferotemporal, superonasal, and inferonasal). Thus, for each retina, 12 rectangles were evaluated, for a total area of 0.48 mm 2 (12 · 0.04 mm 2 ), which is *1% of the total area of the retina, 24 assuming an average area of 50 mm. 2 To determine the density of FG-positive RGCs as cells/mm, 2 we multiplied the number of cells per 0.04 mm 2 by 25.…”

Section: Retrograde Labeling Of Rgcsmentioning

confidence: 99%