Sulforaphane Prevents Angiotensin II-Induced Cardiomyopathy by Activation of Nrf2 Through Epigenetic Modification

Abstract

Nuclear factor erythroid 2-related factor (Nrf2) is an important regulator of cellular antioxidant defense. We previously showed that SFN prevented Ang II-induced cardiac damage via activation of Nrf2. Furthermore, SFN treatment resulted in persistent activation of Nrf2 for at least another 3 months after withdrawing SFN. However, the underlying mechanism of SFN’s persistent cardiac protection remains unclear. This study aimed to explore the potential of SFN in activating cardiac Nrf2 through epigenetic mechanisms. Wild-type mice were injected subcutaneously with Ang II (0.5 mg/kg) every other day for 2 months, with or without SFN (0.5 mg/kg) treatment for 5 days each week for 3 months, and then kept for another 3 month. Administration of a subpressor dose of Ang II induced cardiac inflammatory factor expression, oxidative damage, fibrosis, and cardiac remodeling and dysfunction, all of which were effectively improved by SFN treatment, coupled with an upregulation of Nrf2 and downstream genes (CAT, HO-1). Bisulfite genome sequencing (BGS) and chromatin immunoprecipitation (ChIP) were then performed to detect the methylation level of the first 15 CpGs and histone H3 acetylation (Ac-H3) status in the Nrf2 promoter region, respectively. The results showed that SFN reduced Ang II-induced CpG hypermethylation and promoted Ac-H3 accumulation in the Nrf2 promoter region, accompanied by the inhibition of global DNMT and HDAC activity, and a decreased protein expression of key DNMT and HDAC enzymes: DNMT3a, DNMT3b and HDAC2, HDAC3, HDAC5. Taken together, SFN exerts its cardioprotective effect through epigenetic modification of Nrf2, which may partially contribute to long-term activation of cardiac Nrf2. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant number 395 81570344); National Key RD the Education Department Foundation of Jilin Province (Grant number JJKH20201036KJ); the Fundamental Research Funds for the Central Universities of Jilin University; the Health and Family Planning Commission of Jilin Province Foundations (Grant number 2016Q034 and 2017J11) and the Jilin Provincial Science and Technology Foundations (Grant number 20180414039GH and 20190201200JC). Declaration of Interests: The authors report no conflicts of interest in this work. Ethics Approval Statement: All animal procedures were approved by the Animal Care and Use Committee of the Chinese Academy of Medical Sciences (Beijing, China).