Histone Methylation and Oxidative Stress in Cardiovascular Diseases

Abstract

Oxidative stress occurs when ROS overproduction overwhelms the elimination ability of antioxidants. Accumulated studies have found that oxidative stress is regulated by histone methylation and plays a critical role in the development and progression of cardiovascular diseases. Targeting the underlying molecular mechanism to alter the interplay of oxidative stress and histone methylation may enable creative and effective therapeutic strategies to be developed against a variety of cardiovascular disorders. Recently, some drugs targeting epigenetic modifiers have been used to treat specific types of cancers. However, the comprehensive signaling pathways bridging oxidative stress and histone methylation need to be deeply explored in the contexts of cardiovascular physiology and pathology before clinical therapies be developed. In the present review, we summarize and update information on the interplay between histone methylation and oxidative stress during the development of cardiovascular diseases such as atherosclerosis, coronary artery disease, pulmonary hypertension, and diabetic macro- and microvascular pathologies.

Figure 1

Histone methylation plays an important role in the initiation and progression of atherosclerosis (MLL2: myeloid/lymphoid or mixed-lineage leukemia 2; MLL4: myeloid/lymphoid or mixed-lineage leukemia 4; SMCs: smooth muscle cells).

Figure 2

Oxidative stress under the regulation of histone methylation is increasingly being recognized as a target for cardioprotection in MIRI. The upregulation of NOX2/4 and iNOS modulated by KDM3A and ASH, respectively, contributes to oxidative stress in the development of MIRI. The transcription of SOD1/2 and HO-1 is regulated by SUV39h1 and SEDT7, respectively, which accelerates the degradation and removal of ROS in MIRI (ASH: absent small and homeotic; BRG1: Brahma-Related Gene-1; HO-1: heme oxygenase-1; Keap1: Kelch-like ECH-associated protein 1; KDM3A: lysine demethylase 3A; MIRI: myocardial ischemia-reperfusion injury; MRTF-A: myocardin-related transcription factor A; Nrf-2: nuclear factor erythroid 2-related factor 2; NOX2/4: NADPH oxidase 2/4; ROS: reactive oxygen species; SETD7: SET domain containing lysine methyltransferase 7; SIRT1: Sirtuin-1; SOD1/2: superoxide dismutase 1/2; SUV39h1: suppressor of variegation 3-9 homolog 1; TIP60: Tat-interacting protein 60).

Figure 3

Histone methylation modulates oxidative stress in diabetic endothelial dysfunction and vascular complications. High levels of MMP-9 and TxnIP due to upregulation by LSD1 and EZH2 increase ROS overproduction in diabetic microvascular pathology. The expression and activity of Mn-SOD are decreased by both SUV420h2 and LSD1 in diabetic retinopathy. The Nrf2/Keap1 signaling pathway eliminates ROS in diabetic patients with retinopathy. KDM5A and SET7/9 both modulate the Nrf2/Keap1 signaling pathway and thus influence GSH biosynthesis (COX2: cyclooxygenase-2; EZH2: enhancer of zeste homolog 2; GSH: glutathione; Keap1: Kelch-like ECH-associated protein 1; KDM5A: lysine demethylase 5A; LSD1: lysine-specific demethylase 1; MMP-9: matrix metalloproteinase-9; NOX4: NADPH oxidase 4; ROS: reactive oxygen species; SET7/9: (su(var)-3-9,enhancer-of-zeste,trithorax) domain-containing protein 7/9; SOD3: superoxide dismutase 3; SP-1: specificity protein-1; SUV39H1: suppressor of variegation 3-9 homolog 1; SUV420H2: suppressor of variegation 4-20 homolog 2; TxnIP: thioredoxin-interacting protein).