Quick Links

Li Lab

Research

Ji Li Lab research

Overview

We primarily seek to understand the molecular mechanisms of coronary artery disease (CAD), the most common cause of age-related cardiovascular disease. Our group studies the signaling mechanisms underlying the reduced tolerance elderly patients' hearts show to stress from restricted blood flow (ischemia) and the restoration of normal blood flow (reperfusion), and from pressure-induced hypertension-related heart failure. The goal is to elucidate the molecular mechanisms responsible for activation of an energy sensor, AMP-activated protein kinase (AMPK), identify novel downstream AMPK targets, and develop therapeutic techniques that target the enzyme to prevent and treat myocardial ischemia, hypertension, cardiac hypertrophy, and diabetes.

  • Sirtuin Signaling in Cardiac Metabolism

    Sirtuin family members protect cardiomyocyte function against ischemia and reperfusion injury. C57BL/6J wild type mice, inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1-/-), and cardiomyocyte-specific SIRT3 knockout(cSIRT3-/-) mice are subjected to isolate cardiomyocytes. The deletion of SIRT1 or SIRT3 in cardiomyocytes impairs cardiac contractility during ischemic stress. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 in aging leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to stress.

  • Sestrin2 Maintains Mitochondrial Integrity

    A novel stress-inducible protein Sesn2 declines with aging in the heart that contributes to an age-related intolerance to ischemic insults. This study characterizes the role of Sesn2 in maintaining mitochondrial functional integrity during ischemia and reperfusion in aging. The study reveals that ischemia reperfusion stress triggers Sesn2 accumulation in mitochondria. The association of Sesn2 with OXPHOS Complex I and Complex II altered with aging that results in alterations in mitochondria respiratory function and TCA related enzyme activities. Sesn2 plays a key role in an adaptive metabolic response to ischemia reperfusion stress through maintaining mitochondrial integrity. The results could advance our understanding of Sesn2 serving as a stress inducible scaffold protein to modulate adaptive signaling pathways in the heart under stress conditions. The study will provide a basis that Sesn2 could be a target for increasing heart’s resistance to ischemic insults in the elderly.

  • The Beneficial Effects of Empagliflozin and Metformin on Cardiac Functions

    Empagliflozin (EMPA) and metformin have been revealed to benefit cardiac function in heart failure besides their anti-diabetes activity in some clinical trials. However, the pharmacological mechanisms of Empagliflozin and/or metformin on obesity-related cardiac dysfunction are incompletely understood. We characterize the role of Sestrn2-AMPK-mTOR signaling cascade in mediating the beneficial effects of EMPA and/or metformin on high fat diet (HFD)-induced obesity related cardiac functions. Intriguingly, EMPA can ameliorate obesity related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling pathway. We also attempt to understand the roles and mechanism of metformin improve metabolic syndrome heart from ischemic insults by modulating substrate metabolism, leading to determine a future drug as a target of ischemic injury in the setting of metabolic syndrome.

  • Activated Protein C Signal Transduction in Aging

    Activated protein C (APC) is a plasma serine protease with anticoagulant and anti-inflammatory activities. Endothelial protein C receptor (EPCR) mediates APC's downstream anti-inflammatory effects. We have found that APC exerts cardioprotective effects during ischemia and reperfusion. APC, signaling-selective APC-2Cys, or anticoagulant-selective APC-E170A were bioengineer generated. Serum EPCR measurement showed that membrane EPCR's shedding into circulation was dramatically promoted during ischemia and reperfusion stress. Administration of APC reduced EPCR shedding caused by ischemic stress in wild type but not in EPCRR84A/R84A knock-in heart. The metabolomics analysis and working perfusion heart results demonstrated that AMP-activated protein kinase (AMPK) signaling mediates acute adaptive metabolic response while protein kinase B (Akt) signaling pathway is involved in chronic metabolic programming in the hearts treated with APC derivatives. Therefore, administration of APC could be critical for limiting cardiac damage in aging.

Selected Publications

Ren D, Fedorova J, Davitt K, Le TNV, Griffin J, Liaw PC, Esmon CT, Rezaie AR, Li J. Activated protein C strengthens cardiac tolerance to ischemic insults in aging. Cir Res 2022;130(2): doi: 10.1161/CIRCRESAHA.121.319044PubMed PMID: 34930019

Zhang J, He Z, Fedorova J, Logan C, Bates L, Davitt K, Le V, Murphy J, Li M, Wang M, Lakatta EG, Ren D, Li J. Alterations in mitochondrial dynamics with age-related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility. Aging Cell 2021; 20: e13419. doi:10.1111/acel.13419. PubMed PMID:34316536

Ren D, He Z, Fedorova J, Zhang J, Wood E, Zhang X, Kang DE, Li J. Sestrin2 maintains OXPHOS integrity to modulate cardiac substrate metabolism during ischemia and reperfusion. Redox Biol. 2021;38:101824. Epub 2020/12/15. doi: 10.1016/j.redox.2020.101824. PubMed PMID: 33316744; PMCID: PMC7734306.

Xu B, Li M, Wang Y, Zhao M, Morotti S, Shi Q, Wang Q, Barbagallo F, Teoh JP, Reddy GR, Bayne EF, Liu Y, Shen A, Puglisi JL, Ge Y, Li J, Grandi E, Nieves-Cintron M, Xiang YK. GRK5 Controls SAP97-Dependent Cardiotoxic beta1 Adrenergic Receptor-CaMKII Signaling in Heart Failure. Circ Res. 2020;127(6):796-810. Epub 2020/06/09. doi: 10.1161/CIRCRESAHA.119.316319. PubMed PMID: 32507058; PMCID: PMC7484403.

Han Y, Sun W, Ren D, Zhang J, He Z, Fedorova J, Sun X, Han F, Li J. SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion. Redox Biol. 2020;34:101538. Epub 2020/04/24. doi: 10.1016/j.redox.2020.101538. PubMed PMID: 32325423; PMCID: PMC7176991.

Sun X, Han F, Lu Q, Li X, Ren D, Zhang J, Han Y, Xiang YK, Li J. Empagliflozin Ameliorates Obesity-Related Cardiac Dysfunction by Regulating Sestrin2-Mediated AMPK-mTOR Signaling and Redox Homeostasis in High-Fat Diet-Induced Obese Mice. Diabetes. 2020;69(6):1292-305. Epub 2020/04/03. doi: 10.2337/db19-0991. PubMed PMID: 32234722.

Li J, Qi D, Cheng H, Hu X, Miller EJ, Wu X, Russell KS, Mikush N, Zhang J, Xiao L, Sherwin RS, Young LH. Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart. Proc Natl Acad Sci U S A. 2013;110(40):16133-8. doi: 10.1073/pnas.1312775110. PubMed PMID: 24043794; PMCID: 3791748.