Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

Abstract

Inhibition of total histone deacetylases (HDACs) was phenomenally associated with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to determine whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevent DCM. Type 1 diabetes OVE26 and age-matched wild-type mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 months. These mice were then sacrificed immediately or 3 months later for cardiac function and pathological examination. HDAC3 activity was significantly increased in the heart of diabetic mice. Administration of RGFP966 significantly prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy and fibrosis, along with diminished cardiac oxidative stress, inflammation, and insulin resistance, not only in the mice sacrificed immediately or 3 months later following the three-month treatment. Furthermore, phosphorylated extracellular signal-regulated kinases (ERK) 1/2, a well-known initiator of cardiac hypertrophy, was significantly increased, while dual specificity phosphatase 5 (DUSP5), an ERK1/2 nuclear phosphatase, was substantially decreased in diabetic hearts. Both of these changes were prevented by RGFP966. Chromatin immunoprecipitation assay showed that HDAC3 inhibition elevated histone H3 acetylation on the DUSP5 gene promoter at both two-time points. These findings suggest that diabetes-activated HDAC3 inhibits DUSP5 expression through deacetylating histone H3 on the primer region of DUSP5 gene, leading to the derepression of ERK1/2 and the initiation of DCM. This study indicates the potential application of HDAC3 inhibitor for the prevention of DCM.

Emerging Evidence of Epigenetic Modifications in Vascular Complication of Diabetes

“…Xu et al have reported significantly increased cardiac HDAC3 activity in the OVE26 diabetic mice. They showed that HDAC3 was exerting its pro-hypertrophic activity by downregulating DUSP5 (a MAP Kinase phosphatase) expression, by deacetylation of histone H3 in the primer region of DUSP5 gene ( 10 ). There are several studies showing beneficial and preventive effects of HDAC inhibition on diabetes-induced cardiovascular function.…”

“…DUSP 5 is a dual-specific phosphatase which dephosphorylates and inactivates ERK1/2 MAP Kinase, a known promoter of cardiac hypertrophy ( 10 ). Xu et al recently reported that HDAC3 inhibition with its selective inhibitor, RGFP966, increased the expression of MAP kinase phosphatase, DUSP 5 and prevented development of diabetic cardiomyopathy in Type 1 diabetes OVE26 mice, suggesting a therapeutic potential of HDAC3 inhibition in prevention of diabetic cardiomyopathy ( 10 ).…”

Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis

“…HDAC inhibitors have been studied extensively in the treatment of malignancy, and some have gained approval as antitumor therapies (18). Recently, several studies have also demonstrated that HDAC inhibitors are effective in attenuating the development and progression of fibrosis in several organs, including kidney, heart, and lung (19)(20)(21)(22). Most of those observations, however, are based on the use of pan-HDAC inhibitors.…”

Deletion of RasGRF1 Attenuated Interstitial Fibrosis in Streptozotocin-Induced Diabetic Cardiomyopathy in Mice through Affecting Inflammation and Oxidative Stress

“…Patients with diabetes exhibit chronic low-grade inflammation [ 23 , 24 , 25 , 26 , 27 , 28 ]. The diabetic cardiomyopathy is characterized by diastolic dysfunction in humans, and is caused by myocardial stiffness by interstitial and perivascular fibrosis, which themselves are caused by reactive fibrotic processes, even without the loss of cardiomyocytes (with preserved left ventricular systolic function) [ 7 , 8 , 9 ].…”

“…Hyperglycemia-induced inflammatory and oxidative stress can cause substaintial transcriptional changes in the cells, resulting in an augmented production of cytokines, including several inflammatory mediators (MCP-1 and CCL5). In DCM, these mediators induced infiltration of the inflammatory cells into the myocardium, where they secrete inflammatory cytokines through the phosphorylation of ERK2/3 pathways in diabetic cardiomyopathy [ 23 , 24 , 29 ]. Our results are consistent with previous findings [ 23 , 24 , 29 ] and demonstrate that DM induces chronic inflammation that can cause substantial functional and structural alterations in the heart tissue.…”