Histone deacetylase 3 (HDAC3) and silent information regulator 1 (SIRT1) are histone deacetylases that regulate important metabolic pathways and play important roles in diabetes and myocardial ischemia/reperfusion (IR) injury. In this study, we explored the protective mechanism of Bmal1-regulated autophagy mediated by the HDAC3/SIRT1 pathway in myocardial IR injury of diabetic rats.
Methods and results
Type 1 diabetes was established by administering an intraperitoneal injection of streptozotocin. After 8 weeks, the left anterior descending coronary artery was ligated for 30 min and reperfused for 120 min to establish a myocardial IR injury model in diabetic rats. H9c2 cardiomyocytes were exposed to high glucose concentration (30 mM) and hypoxia/reoxygenation (H/R) stimulation in vitro. The myocardial infarct size and levels of serum cTn-I, CK-MB, and LDH in diabetic rats subjected to myocardial IR injury were significantly higher. Upregulated HDAC3 and downregulated SIRT1 expression were observed in diabetic and IR hearts, along with a lower Bmal1 level. Autophagy was rapidly increased in the hearts of diabetic or non-diabetic rats in the IR group compared with the sham group, but significantly attenuated in the hearts of diabetic rats compared with the hearts of non-diabetic rats after IR insult. Consistent with decreased autophagy, we observed increased HDAC3 expression and decreased SIRT1 and Bmal1 levels in the myocardial tissue of diabetic rats after IR. Inhibition of HDAC3 by the inhibitor RGFP966 and activation of SIRT1 by the agonist SRT1720 could significantly attenuate myocardial IR injury in diabetic rats by restoring Bmal1-regulated autophagy.
Based on these findings, the disordered HDAC3/SIRT1 circuit (upregulated HDAC3 and downregulated SIRT1 levels) plays an important role in aggravating myocardial IR injury in diabetic rats by downregulating Bmal1-mediated autophagy. Treatments targeting HDAC3/SIRT1 to activate the autophagy may represent a novel strategy to alleviate myocardial IR injury in diabetes.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
The used and/or analyzed datasets are available from the corresponding author on reasonable request.
Fares MA. Introduction: Challenges and advances in cardiovascular disease. Cleve Clin J Med. 2017;84(12 Suppl 3):11.
Bugger H, Pfeil K. Mitochondrial ROS in myocardial ischemia reperfusion and remodeling. Biochim Biophys Acta Mol basis Dis. 1866;2020(7):165768.
Godoy LC, Lawler PR, Farkouh ME, Hersen B, Nicolau JC, Rao V. Urgent revascularization strategies in patients with diabetes mellitus and acute coronary syndrome. Can J Cardiol. 2019;35(8):993–1001.
Xing W, Tan Y, Li K, Tian P, Tian F, Zhang H. Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice. J Mol Cell Cardiol. 2020;S0022-2828(20):30057–2.
Penna C, Andreadou I, Aragno M, Beauloye C, Bertrand L, Lazou A, et al. Effect of hyperglycaemia and diabetes on acute myocardial ischemia-reperfusion injury and cardioprotection by ischaemic conditioning protocols. Br J Pharmacol. 2020;27:5312–35.
Emmett MJ, Lazar MA. Integrative regulation of physiology by histone deacetylase 3. Nat Rev Mol Cell Biol. 2019;20(2):102–15.
Bocchi L, Motta BM, Savi M, Vilella R, Meraviglia V, Rizzi F, et al. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restores cardiomyocyte contractility in a rat model of early diabetes. Int J Mol Sci. 2019;20(8). https://doi.org/10.3390/ijms20081873.
Xu Z, Tong Q, Zhang Z, Zhang Z, Wang S, Zheng Y, et al. Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway. Clin Sci (Lond). 2017;131(15):1841–57.
Su Q, Liu Y, Lv XW, Dai RX, Yang XH, Kong BH. LncRNA TUG1 mediates ischemic myocardial injury by targeting miR-132-3p/HDAC3 axis. Am J Physiol Heart Circ Physiol. 2020;318(2):H332–44.
Sharifi-Sanjani M, Shoushtari AH, Quiroz M, Baust J, Sestito SF, Mosher M, et al. Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3. J Am Heart Assoc. 2014;3(3):e000670. https://doi.org/10.1161/JAHA.113.000670.
Xie M, Kong Y, Tan W, May H, Battiprolu PK, Pedrozo Z, et al. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation. 2014;129(10):1139–51.
Chen M, Liu Q, Chen L, Zhang L, Cheng X, Gu E. HDAC3 mediates cardioprotection of remifentanil postconditioning by targeting GSK-3β in H9c2 cardiomyocytes in hypoxia/reoxygenation injury. Shock. 2018;50(2):240–7.
Meng X, Tan J, Li M, Song S, Miao Y, Zhang Q. Sirt1: role under the condition of ischemia/hypoxia. Cell Mol Neurobiol. 2017;37(1):17–28.
Ren Q, Hu Z, Jiang Y, Tan X, Botchway BOA, Amin N, et al. SIRT1 protects against apoptosis by promoting autophagy in the oxygen glucose deprivation/reperfusion-induced injury. Front Neurol. 2019;10:1289.
Yu LM, Dong X, Xue XD, Zhang J, Li Z, Wu HJ, et al. Protection of the myocardium against ischemia/reperfusion injury by punicalagin through an SIRT1-NRF-2-HO-1-dependent mechanism. Chem Biol Interact. 2019;306:152–62.
Aguilar-Arnal L, Katada S, Orozco-Solis R, Sassone-Corsi P. NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1. Nat Struct Mol Biol. 2015;22(4):312–8.
Zhou B, Zhang Y, Zhang F, Xia Y, Liu J, Huang R, et al. CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1[J]. Hepatology. 2014;59(6):2196–206.
Harfmann BD, Schroder EA, Kachman MT, Hodge BA, Zhang X, Esser KA. Muscle-specific loss of Bmal1 leads to disrupted tissue glucose metabolism and systemic glucose homeostasis. Skelet Muscle. 2016;6:12.
Song F, Xue Y, Dong D, Liu J, Fu T, Xiao C, et al. Insulin restores an altered corneal epithelium circadian rhythm in mice with streptozotocin-induced type 1 diabetes. Sci Rep. 2016;6:32871.
Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice. Diabetes Obes Metab. 2011;13(12):1097–104.
Kung TA, Egbejimi O, Cui J, Ha NP, Durgan DJ, Essop MF, et al. Rapid attenuation of circadian clock gene oscillations in the rat heart following ischemia-reperfusion. J Mol Cell Cardiol. 2007;43(6):744–53.
McGinnis GR, Tang Y, Brewer RA, et al. Genetic disruption of the cardiomyocyte circadia clock differentially influences insulin-mediated processes in the heart. J Mol Cell Cardiol. 2017;110:80–95.
Lim H, Lim YM, Kim KH, Jeon YE, Park K, Kim J, et al. A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes. Nat Commun. 2018;9(1):1438.
Bravo-San Pedro JM, Kroemer G, Galluzzi L. Autophagy and mitophagy in cardiovascular disease. Circ Res. 2017;120(11):1812–24.
Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress? Nat Med. 2007;13(5):619–24.
Zhang Y, Liu D, Hu H, Zhang P, Xie R, Cui W. HIF-1α/BNIP3 signaling pathway-induced-autophagy plays protective role during myocardial ischemia-reperfusion injury. Biomed Pharmacother. 2019;120:109464.
Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 2007;100(6):914–22.
Ham PB 3rd, Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol. 2017;157:92–116.
Gu S, Tan J, Li Q, Liu S, Ma J, Zheng Y, et al. Downregulation of LAPTM4B contributes to the impairment of the autophagic flux via unopposed activation of mTORC1 signaling during myocardial ischemia/reperfusion injury. Circ Res. 2020;127(7):e148–65.
Zhou B, Lei S, Xue R, Leng Y, Xia Z, Xia ZY. DJ-1 overexpression restores ischaemic post-conditioning-mediated cardioprotection in diabetic rats: role of autophagy. Clin Sci (Lond). 2017;131(11):1161–78.
Qiu Z, Lei S, Zhao B, Wu Y, Su W, Liu M, et al. NLRP3 inflammasome activation-mediated pyroptosis aggravates myocardial ischemia/reperfusion injury in diabetic rats. Oxidative Med Cell Longev. 2017;2017:9743280–17.
Qiu Z, He Y, Ming H, Lei S, Leng Y, Xia ZY. Lipopolysaccharide (LPS) aggravates high glucose- and hypoxia/reoxygenation-induced injury through activating ROS-dependent NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. J Diabetes Res. 2019;2019:8151836–12.
Dávalos-Salas M, Montgomery MK, Reehorst CM, Nightingale R, Ng I, Anderton H, et al. Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity. Nat Commun. 2019;10(1):5291.
Lkhagva B, Kao YH, Lee TI, Lee TW, Cheng WL, Chen YJ. Activation of class I histone deacetylases contributes to mitochondrial dysfunction in cardiomyocytes with altered complex activities. Epigenetics. 2018;13(4):376–85.
Sathishkumar C, Prabu P, Balakumar M, Lenin R, Prabhu D, Anjana RM, et al. Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes. Clin Epigenetics. 2016;8:125.
Kosgei VJ, Coelho D, Guéant-Rodriguez RM, Guéant JL. Sirt1-PPARS Cross-talk in complex metabolic diseases and inherited disorders of the one carbon metabolism. Cells. 2020;9(8):1882.
Ding M, Lei J, Han H, Li W, Qu Y, Fu E, et al. SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats. Cardiovasc Diabetol. 2015;14:143.
Zhang B, Zhai M, Li B, Liu Z, Li K, Jiang L, et al. Honokiol ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by reducing oxidative stress and apoptosis through activating the SIRT1-Nrf2 signaling pathway. Oxidative Med Cell Longev. 2018;2018:3159801–16.
Li D, Wang X, Huang Q, Li S, Zhou Y, Li Z. Cardioprotection of CAPE-oNO(2) against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-κB pathway in vivo and in vitro. Redox Biol. 2018;15:62–73.
He Q, Li Z, Wang Y, Hou Y, Li L, Zhao J. Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. Int Immunopharmacol. 2017;50:208–15.
Chen-Scarabelli C, Agrawal PR, Saravolatz L, Abuniat C, Scarabelli G, Stephanou A, et al. The role and modulation of autophagy in experimental models of myocardial ischemia-reperfusion injury. J Geriatr Cardiol. 2014;11(4):338–48.
Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J. Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One. 2014;9(6):e98972. https://doi.org/10.1371/journal.pone.0098972.
Huang Z, Han Z, Ye B, Dai Z, Shan P, Lu Z, et al. Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes. Eur J Pharmacol. 2015;762:1–10.
Foteinou PT, Venkataraman A, Francey LJ, Anafi RC, Hogenesch JB, Doyle FJ. Computational and experimental insights into the circadian effects of SIRT1. Proc Natl Acad Sci USA. 2018;11545(45). https://doi.org/10.1073/pnas.1803410115.
Shi G, Xie P, Qu Z, Zhang Z, Dong Z, An Y, et al. Distinct roles of HDAC3 in the core circadian negative feedback loop are critical for clock function. Cell Rep. 2016;14(4):823–34.
Ma D, Lin JD. Circadian regulation of autophagy rhythm through transcription factor C/EBPbeta. Autophagy. 2012;8(1):124–5.
This study was supported by grants from the National Natural Science Foundation of China (81970722 and 81671891).
The care of animals and all animal experiments were implemented after being reviewed and approved by the Laboratory Animal Welfare & Ethics Committee (IACUC) of Renmin Hospital of Wuhan University.
Consent to Participate
Consent for Publication
Conflict of Interest
The authors declare no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Qiu, Z., Ming, H., Zhang, Y. et al. The Protective Role of Bmal1-Regulated Autophagy Mediated by HDAC3/SIRT1 Pathway in Myocardial Ischemia/Reperfusion Injury of Diabetic Rats. Cardiovasc Drugs Ther (2021). https://doi.org/10.1007/s10557-021-07159-1
- Myocardial ischemia reperfusion injury