Dr. Gao's Laboratory

RESEARCH INTERESTS

• Cardiovascular physiology and pathophysiology: sympathetic activity, blood pressure regulation, hypertension, chronic heart failure, cardiac ischemia/reperfusion.

• Exercise beneficial influence on blood vessel, heart, and skeletal muscle: post-exercise hypotension, cardiac protection, muscle contractility, sarcopenia amelioration.

• Implication and significance of Nrf2 and extracellular vesicles (EVs) in exercise, skeletal muscle, cardiovascular function: Nrf2-maintained cellular redox homeostasis and antioxidant defenses; EV-mediated protein/miRNA transfer from skeletal muscle to blood vessel/heart/brainstem during exercise.

RESEARCH STATEMENT

Physical activity is fundamental for the maintenance of human health. Regular exercise reduces cardiovascular risk and improves disease prognosis. The goal of our laboratory is to elucidate a novel mechanism underpinning exercise-evoked cardiovascular benefits involved in nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and extracellular vesicles (EVs) in skeletal muscle. We hypothesize that, during exercise, contracting muscle generates a mass of reactive oxygen species (ROS), which in turn activate Nrf2 to upregulate a large group of antioxidant enzymes and other cytoprotective proteins. These proteins are packaged into EVs and transported to the remote tissues/organs where antioxidant defenses are enhanced and protective processes occurred.  

Novel mechanism underlying exercise-cardiovascular benefits

LAB PERSONNEL

Anjali Bhat, PhD Post-doctoral Research Associate	Li Yu, BS Research Technologist I

Ved Pendyala High School Researcher Research Intern	Sarah Pribil PhD Student

ALUMNI

Will Bruening Medical Student Summer 2022 Research Intern	Brenden Lofgren Medical Student Summer 2022 Research Intern

 LAB TECHNIQUES

• Rodent animal models of cardiovascular diseases (Cardiac I/R, coronary artery ligation, hypertension);
• Skeletal muscle specific transgenic mouse models (GPF reporter, Nrf2 KO/OE).
• Small animal surgeries for survival and terminal experiments (carotid and femoral arterial cannulation, telemetry unit implantation).
• Cardiovascular measurement in conscious and anesthesia conditions (BP, HR, ECG, RSNA, LVEDP).
• Biochemistry analyses of protein and nucleic acid (Western blot, ELISA, PCR, RT-PCR, quantitative PCR).
• Immunofluorescence staining and confocal microscopy (Leica TCS SPE-II).
• Isolation and analyses of extracellular vesicles from tissue, plasma, cells, and culture medium (Beckman Optima XPN Ultracentrifuge, ZetaView nanoparticle tracking analyzer).

LAB NEWS

Team Photo

As a Principle Investigator (PI)

• January 2022 – December 2025

Skeletal Muscle Nrf2: Exercise-Induced Cardiovascular Protection

DHHS/NIH/NHLBI (R01HL160820)

$2,070,556

• July 2019 – June 2021

Chronic Exercise-Induced Skeletal Muscle Functional and Proteomic Adaptation: Role of Nrf2/Keap1

University of Nebraska Medical Center, College of Medicine; Frances E. Lageschulte and Evelyn B. Weese

New Frontiers in Medical Research Fund

$55,000

• April 2009 – March 2014

AT2 Receptors in the RVLM: Regulation of Sympathetic Outflow in Heart Failure

DHHS/NIH/NHLBI (R01HL093028)

$1,811,708

• July 2006 – June 2010

Sympatho-excitation in chronic heart failure: role of AT1 and AT2 receptors

American Heart Association National Center, Scientist Development Grant (0635007N)

$260,000

• July 2004 – June 2006

Sympathetic outflow in heart failure angiotensin II, NO and ROS

American Heart Association Heartland Affiliate, Postdoctoral Fellowship (0425680Z)

$83,000

As a Co-investigator (Co-I)

• April 2021 – March 2025

Nrf2 regulation of oxidative stress in heart failure and extra vesicular communication

DHHS/NIH/NHLBI (R01HL153176) (PI-Dr. Irving Zucker)

Role: Co-Investigator for 3.00 Calendar Months

• January 2020 – December 2023

Cardiac afferents and renal function in heart failure

DHHS/NIH/NHLBI (R01HL126796) (PI-Dr. Irving Zucker)

Role: Co-Investigator for 1.80 Calendar Months

• April 2020 – March 2023

Novel Neural Mechanisms underlying Lung-Heart Pathological Crosstalk

DHHS/NIH/NHLBI (R01HL152160) (PI-Dr. Hanjun Wang)

Role: Co-Investigator for 1.20 Calendar Months

• April 1999 – March 2022

Neural Control of the Circulation in Heart Failure

DHHS/NIH/NHLBI (P01-HL62222) (PI-Dr. Irving Zucker)

Li

Role 2: Project 1. Co-Investigator: 1.2 calendar months

REPRESENTATIVE PUBLICATIONS
(Past two years)

Tian C, Gao L, Rudebush TL, Yu L, Zucker IH (2022). Extracellular Vesicles Regulate Sympatho-Excitation by Nrf2 in Heart Failure. Circ Res. 2022;131:687-700. PMID: 36098045

Xia Z, Vellichirammal NN, Han L, Gao L, Boesen EI, Schiller AM, Pellegrino PR, Lisco SJ, Guda C, Zucker IH, Wang HJ (2022). Cardiac Spinal Afferent Denervation Attenuates Renal Dysfunction in Rats With Cardiorenal Syndrome Type 2. JACC Basic Transl Sci. 2022;7:582-596. PMID: 35818505

Chen XY, Lin C, Liu GY, Pei C, Xu GQ, Gao L, Wang SZ, Pan YX (2022). ACE2 gene combined with exercise training attenuates central AngII/AT1 axis function and oxidative stress in a prehypertensive rat model. J Appl Physiol (1985). 2022;132:1460-1467. PMID: 35546127

Gao L, Wang HJ, Tian C, Zucker IH (2021). Skeletal Muscle Nrf2 Contributes to Exercise-Evoked Systemic Antioxidant Defense Via Extracellular Vesicular Communication. Exerc Sport Sci Rev. 2021;49:213-222. PMID: 33927165

Tian C, Gao L, Zucker IH (2021). Regulation of Nrf2 signaling pathway in heart failure: Role of extracellular vesicles and non-coding RNAs. Free Radic Biol Med. 2021;167:218-231. PMID: 33741451

Hong J, Adam RJ, Gao L, Hahka T, Xia Z, Wang D, Nicholas TA, Zucker IH, Lisco SJ, Wang HJ (2021).

Macrophage activation in stellate ganglia contributes to lung injury-induced arrhythmogenesis in male rats.

Acta Physiol (Oxf). 2021;232:e13657. PMID: 33817984

Abu R, Yu L, Kumar A, Gao L*, Kumar V* (2021). A Quantitative Proteomics Approach to Gain Insight into NRF2-KEAP1 Skeletal Muscle System and Its Cysteine Redox Regulation. Genes (Basel). 2021;12:1655. (*Co-corresponding Author); PMID: 34828261

Hong J, Fu S, Gao L, Cai Y, Lazartigues E, Wang HJ (2021). Voltage-gated potassium channel dysfunction in dorsal root ganglia contributes to the exaggerated exercise pressor reflex in rats with chronic heart failure. Am J Physiol Heart Circ Physiol. 2021;321:H461-H474. PMID: 34270374

Tian C, Hu G, Gao L, Hackfort BT, Zucker IH (2020). Extracellular vesicular MicroRNA-27a* contributes to cardiac hypertrophy in chronic heart failure. J Mol Cell Cardiol. 2020;143:120-131.PMID: 32370947

Gao L*, Kumar V, Vellichirammal NN, Park SY, Rudebush TL, Yu L, Son WM, Pekas EJ, Wafi AM, Hong J, Xiao P, Guda C, Wang HJ, Schultz HD, Zucker IH* (2020). Functional, proteomic and bioinformatic analyses of Nrf2- and Keap1- null skeletal muscle. J Physiol. 2020;598:5427-5451. PMID: 32893883

Hong J, Lisco AM, Rudebush TL, Yu L, Gao L, Kitzerow O, Zucker IH, Wang HJ (2020). Identification of Cardiac Expression Pattern of Transient Receptor Potential Vanilloid Type 1 (TRPV1) Receptor using a Transgenic Reporter Mouse Model. Neurosci Lett. 2020;737:135320. PMID: 32841712

Tian C, Gao L, Zhang A, Hackfort BT, Zucker IH (2019). Therapeutic Effects of Nrf2 Activation by Bardoxolone Methyl in Chronic Heart Failure. J Pharmacol Exp Ther. 2019;371:642-651. PMID: 31601682

Ma A, Hong J, Shanks J, Rudebush T, Yu L, Hackfort BT, Wang H, Zucker IH, Gao L (2019). Upregulating Nrf2 in the RVLM ameliorates sympatho-excitation in mice with chronic heart failure. Free Radic Biol Med. 2019;141:84-92. PMID: 31181253

Wafi AM, Yu L, Gao L, Zucker IH (2019). Exercise training upregulates Nrf2 protein in the rostral ventrolateral medulla of mice with heart failure. J Appl Physiol (1985). 2019;127:1349-1359. PMID: 31556830

Shanks J, de Morais SDB, Gao L, Zucker IH, Wang HJ (2019). TRPV1 (Transient Receptor Potential Vanilloid 1) Cardiac Spinal Afferents Contribute to Hypertension in Spontaneous Hypertensive Rat.

Hypertension. 2019;74:910-920. PMID: 31422690

Wafi AM, Hong J, Rudebush TL, Yu L, Hackfort B, Wang H, Schultz HD, Zucker IH, Gao L (2019). Curcumin improves exercise performance of mice with coronary artery ligation-induced HFrEF: Nrf2 and antioxidant mechanisms in skeletal muscle. J Appl Physiol (1985). 2019;126:477-486.PMID: 30462567

Additional Publications in Pubmed. 

COLLABORATORS

Chittibabu (Babu) Guda, PhD Dept. of Genetics, Cell Biology & Anatomy, UNMC	Vikas Kumar, PhD Dept. of Genetics, Cell Biology & Anatomy, UNMC Mass Spectrometry and Proteomics Core	Song-Young Park, PhD School of Health and Kinesiology, UNO

Dr. Hanjun Wang, MD Dept. of Anesthesiology, UNMC	Dr. Irving H. Zucker, PhD Dept. of Cellular & Integrative Physiology, UNMC