Highlights
- •Histone demethylase KDM3a, a novel regulator of vascular smooth muscle cells, controls vascular neointimal hyperplasia in diabetic rats.
- •KDM3a and H3M9me2 were involved in metabolic memory after vascular injury in diabetic condition.
- •KDM3a expression is closely associated with the development of neointimal hyperplasia in diabetes.
- •KDM3a might function as a key regulator of vascular remodeling in diabetes via Rho/ROCK and AngII/AGTR1 signaling pathways.
Abstract
Background and aims
Deregulation of histone demethylase KDM3a, an important regulator for H3K9 methylation,
is correlated with obesity and abnormal metabolism in rodent models. However, the
function of KDM3a in vascular remodeling under diabetic condition is unknown.
Methods
Adenoviruses expressing KDM3a and lentiviruses expressing KDM3a-targeting siRNA were
generated to study the role of KDM3a both in vivo and in vitro. The carotid artery balloon injury model was established in diabetic SD rats to evaluate
the significance of KDM3a in vascular injury.
Results
Diabetic vessels were associated with sustained loss of histone H3 lysine 9 di-methylation
(H3K9me2) and elevation of KDM3a. This phenomenon was induced by high glucose (HG)
and was persistently present even after removal from diabetic condition and high glucose
in vascular smooth muscle cells (VSMCs). After 28-day balloon injury, KDM3a overexpression
accelerated while KDM3a knockdown reduced neointima formation, following vascular
injury in diabetic rats without glucose control. Microarray analysis revealed KDM3a
altered the expression of vascular remodeling genes; particularly, it mediated the
Rho/ROCK and AngII/AGTR1 pathways. In the in vivo study, HG and Ang II-stimulated proliferation and migration of VSMCs were enhanced
by KDM3a overexpression, whereas markedly prevented by KDM3a knockdown. KDM3a regulated
the transcription of AGTR1 and ROCK2 via controlling H3K9me2 in the proximal promoter regions.
Conclusions
Histone demethylase KDM3a promotes vascular neointimal hyperplasia in diabetic rats
via AGTR1 and ROCK2 signaling pathways. Targeting KDM3a might represent a promising therapeutic approach for the prevention of coronary artery
disease with diabetes.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Primary and secondary prevention of cardiovascular disease in diabetes with aspirin.Diab Vasc. Dis. Res. 2012; 9: 245-255
- ACCORD MIND investigators. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy.Lancet Neurol. 2011; 10: 969-977
- Effects of intensive glucose lowering in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.Circulation. 2010; 122: 844-846
Zoungas S, de Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, MacMahon S, Marre M, Neal B, Patel A, Woodward M, Chalmers J; ADVANCE Collaborative Group, Cass A, Glasziou P, Harrap S, Lisheng L, Mancia G, Pillai A, Poulter N, Perkovic V, Travert F. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: new results from the ADVANCE trial. Diabetes Care 2009; 32: 2068–2074.
- Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N. Engl. J. Med. 2008; 358: 2560-2572
- VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes.N. Engl. J. Med. 2009; 360: 129-139
- Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I.Eur. Heart J. 2013; 34: 2436-2443
- Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II.Eur. Heart J. 2013; 34: 2444-2452
- Cellular and molecular mechanisms of endothelial dysfunction in diabetes.Diab Vasc. Dis. Res. 2013; 10: 472-482
- Epigenetics: mechanisms and implications for diabetic complications.Circ. Res. 2010; 107: 1403-1413
- Epigenetic mechanisms in diabetic vascular complications.Cardiovasc Res. 2011; 90: 421-429
- Translating the histone code.Science. 2001; 293: 1074-1080
- DCCT/EDIC Research Group. Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes.Diabetes. 2014; 63: 1748-1762
- The diverse functions of histone lysine methylation.Nat. Rev. Mol. Cell Biol. 2005; 6: 838-849
- Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes.Diabetes. 2008; 57: 3189-3198
- Epigenetic regulation of vascular endothelial gene expression.Circ. Res. 2008; 102: 873-887
- Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 9047-9052
- The histone demethylase, Jmjd1a, interacts with the myocardin factors to regulate SMC differentiation marker gene expression.Circ. Res. 2007; 101: e115-e123
- Role of Jhdm2a in regulating metabolic gene expression and obesity resistance.Nature. 2009; 458: 757-761
- Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice.Genes Cells. 2009; 14: 991-1001
- Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress.Circ. Res. 2001; 88: 1291-1298
- Inhibition of neointimal hyperplasia in the rat carotid artery injury model by a HMGB1 inhibitor.Atherosclerosis. 2012; 224: 332-339
- Lentivirus-mediated RNAi targeting CREB binding protein attenuates neointimal formation and promotes re-endothelialization in balloon injured rat carotid artery.Cell Physiol. Biochem. 2010; 26: 441-448
- Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs.Circulation. 1998; 98: 919-926
- Overexpression of miR-429 induces mesenchymal-to-epithelial transition (MET) in metastatic ovarian cancer cells.Gynecol. Oncol. 2011; 121: 200-205
- Controlling the false discovery rate: a practical and powerful approach to multiple testing.J. R. Stat. Soc. Ser. B Stat. Methodol. 1995; 57: 289-300
- Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia.J. Exp. Med. 2008; 205: 2409-2417
- Serum deprivation results in redifferentiation of human umbilical vascular smooth muscle cells.Am. J. Physiol. Cell Physiol. 2006; 291: C50-C58
- Aldosterone and angiotensin II synergistically stimulate migration in vascular smooth muscle cells through c-Src-regulated redox-sensitive RhoA pathways.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1511-1518
- Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension.Am. J. Physiol. Heart Circ. Physiol. 2010; 299: H1854-H1864
- Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail.Diabetes. 2009; 58: 1229-1236
- Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension.Am. J. Physiol. Heart Circ. Physiol. 2011; 301: H1862-H1871
- Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages.Cancer Res. 2013; 73: 3019-3028
- The JmjC domain-containing histone demethylase KDM3A is a positive regulator of the G1/S transition in cancer cells via transcriptional regulation of the HOXA1 gene.Int. J. Cancer. 2012; 131: E179-E189
- Physiological role of ROCKs in the cardiovascular system.Am. J. Physiol. Cell Physiol. 2006; 290: C661-C668
- Targeted disruption of ROCK1 causes insulin resistance in vivo.J. Biol. Chem. 2009; 284: 11776-11780
- Crucial role of ROCK2 in vascular smooth muscle cells for hypoxia-induced pulmonary hypertension in mice.Arterioscler. Thromb. Vasc. Biol. 2013; 33: 2780-2791
- Emerging concepts of regulation of angiotensin II receptors: new players and targets for traditional receptors.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 2532-2539
- Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system.Circulation. 2004; 109: 8-13
- The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis.Circulation. 2002; 105: 393-396
- Angiotensin II signal transduction through small GTP-binding proteins: mechanism and significance in vascular smooth muscle cells.Hypertension. 2006; 48: 534-540
- Angiotensin II enhances interleukin-18 mediated inflammatory gene expression in vascular smooth muscle cells: a novel cross-talk in the pathogenesis of atherosclerosis.Circ. Res. 2005; 96: 1064-1071
Article Info
Publication History
Published online: December 09, 2016
Accepted:
December 8,
2016
Received in revised form:
November 23,
2016
Received:
June 10,
2016
Identification
Copyright
© 2016 Elsevier Ireland Ltd. All rights reserved.
