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He - Biosketch

BIOGRAPHICAL SKETCH

NAME: Xiaochen He, Ph.D.

eRA COMMONS USER NAME (credential, e.g., agency login): XIAOCHENHE

POSITION TITLE: Instructor

EDUCATION/TRAINING

Personal Statement

Heart failure is one of the leading causes of death in the United States and worldwide. We found that heart failure development is associated with increased autoreactive lymphocyte infiltration in the heart and lungs. Our overall research objective is to understand the mechanism of autoreactive lymphocytes in regulating cardiopulmonary inflammation, development of heart failure development, and identifying new therapeutic targets to treat heart failure. One of our recent findings is that heart failure is associated with an increase of IFN-γ by several autoreactive lymphocytes, whereas methods (immunotherapy by administration of blocking antibodies or manipulation of gene expression) that suppress these autoreactive lymphocytes were effective in halting cardiopulmonary inflammation, heart failure development, and the consequent progression of heart failure. The findings from this project will advance our understanding of cardiac and pulmonary toxicity during the development of heart failure. Insight into the mechanisms of infiltration of autoreactive lymphocytes and cardiopulmonary toxicity is impactful as most of the identified targets/pathways can be modified by currently available therapeutic approaches.

Positions, Scientific Appointments and Honors

Positions and Employment:

01/2023-present	Instructor, Department of Physiology and Biophysics, UMMC.
04/2021-12/2022	Postdoctoral Fellow, Department of Physiology and Biophysics, UMMC.
08/2017-04/2021	Postdoctoral Fellow, Department of Pharmacology and Toxicology, UMMC
06/2011-07/2012	Researcher II, Departments of Physiology and Biophysics, UMMC.

Honors:

10/2019	Poster Presentation Winner, UMMC Research Day 2019
11/2017	ASN Kidney Star Award, ASN Kidney Week 2017
05/2017	Randall-Trustmark Graduate Research Award, School of Graduate Studies in the Health Sciences, UMMC

05/2017	Excellence in Medical Pharmacology Graduate Student Award, Department of Pharmacology and Toxicology, UMMC
04/2017	APS Cardiovascular Section-Research Recognition Award, Experimental Biology 2017
04/2015	Trainee Research Recognition in Physiological Genomics, Experimental Biology 2015
05/2012	Fundamentals of Physiology Award, School of Graduate Studies in the Health Sciences, UMMC

Professional membership and service:

American Physiological Society (since 2014)
American Heart Association (since 2013)
American Society of Nephrology (since 2017)

Academic Activities:

Ad hoc Reviewer:

2021	European Journal of Pharmacology
2021	Physiological Genomics
2021	International Journal of Molecular Sciences
2020	American Journal of Physiology-Heart and Circulatory Physiology
2020	American Journal of Physiology-Endocrinology and Metabolism
2020	Nutrients
2019	Cells
2019	Biomolecules
2019	Biomedicine & Pharmacotherapy
2019	Journal of Applied Physiology

Peer Reviewer Board:

2021- Current Cells

Committee:

Poster Judge, Student Award, Council for High Blood Pressure, 2017

Contributions to Science

30 publications (co-author-22).

C1. The role of natural killer (NK) cells in regulating cardiac and lung inflammation.NK cells play an important role in regulating immune response, but the role of NK cells in heart failure development is not totally clear. We recently studied the genomic prefile using single cell RNA-seq. We found that NK cells are genetically and metabolically reprogramed during heart failure development. We have further investigated the effect of NK cell depletion by using well-documented monoclonal blocking antibodies and characterized the effect of NK cells on cardiac and lung inflammation, and cardiac dysfunction in mice after chronic systolic overload produced by Transverse Aortic Constriction (TAC).

1. He X*, Xu R*, Pan L, Bhattarai U, Liu X, Zeng H, Chen JX, Hall ME, Chen Y. Inhibition of NK1.1 Signaling Attenuates Pressure Overload-Induced Cardiopulmonary Inflammation, Pulmonary IFN-γ Production, and Heart Failure Progression. Front Immunol. 2023. *Equal contribution. Under minor
2. Bhattarai U*, He X*, Xu R, Liu X, Pan L, Sun Y, Chen JX, Chen Y. IL-12α deficiency attenuates pressure overload-induced cardiac inflammation, hypertrophy, dysfunction, and heart failure progression. Front Immunol. 2023 Feb 13;14:1105664. doi: 10.3389/fimmu.2023.1105664. PMID: 36860846. *Equal contribution.

C2. Mechanism and potential therapeutic option for heart failure with preserved ejection fraction.During the last couple of years on my graduate study, my interest was to investigate the role of SIRT3 on endothelial cell (EC) metabolism and diastolic function. The goal was to test the hypothesis that loss of SIRT3 in ECs alters endothelial metabolism and function thus contributes to the development of diastolic dysfunction. We found that SIRT3 regulates a metabolic switch between mitochondrial respiration and glycolysis associated with a reduction in the expression of glycolytic enzyme PFKFB3 and a fall in glycolysis. In vivo, endothelial-specific SIRT3 KO (ECKO) mice exhibited reduced coronary flow reserve (CFR) and developed diastolic dysfunction, associated with significantly increased perivascular fibrosis in the coronary artery. Diastolic dysfunction is emerging as a leading cause of heart failure in aging population. So far, there is no effective treatment for diastolic dysfunction in the patients with heart failure. Induction of hypoxia tolerance and reprogrammed cell metabolisms have emerged as novel therapeutic strategies for the treatment of cardiovascular diseases. Therefore, we investigated the role of hypoxic regulator prolyl hydroxylase domain-containing protein (PHD) in the reprogramming of endothelial metabolism and diastolic function in the SIRT3 knockout mice. Our work indicates that inhibition of PHD and reprogrammed cell metabolisms ameliorate the diastolic dysfunction in SIRT3 deficiency and provides a potential therapeutic strategy of induction of hypoxia tolerance for patients with diastolic dysfunction associated with coronary microvascular dysfunction, especially in the aging population with reduced SIRT3. I have prepared two first-authored manuscripts from this work. In addition, our most recent study indicates that endothelial SIRT3 dictates the transportation of glucose to cardiomyocyte under chronic stress and that loss of SIRT3 exacerbates pressure overload-induced heart failure.

1. He X,Zeng H, Cantrell AC, Williams QA, Chen Knockout of TIGAR enhances myocardial phosphofructokinase activity and preserves diastolic function in heart failure. J Cell Physiol. 2022 Aug;237(8):3317-3327. doi: 10.1002/jcp.30790. Epub 2022 May 27. PubMed PMID: 35621078.
2. He X,Zeng H, Cantrell AC, Chen Regulatory role of TIGAR on endothelial metabolism and angiogenesis. J Cell Physiol. 2021 Apr 30;. doi: 10.1002/jcp.30401. [Epub ahead of print] PubMed PMID: 33928637.
3. He X,Zeng H, Roman RJ, Chen Inhibition of prolyl hydroxylases alters cell metabolism and reverses pre- existing diastolic dysfunction in mice. Int J Cardiol. 2018 Dec 1;272:281-287. doi: 10.1016/j.ijcard.2018.08.065. Epub 2018 Aug 24. PubMed PMID: 30177233; PubMed Central PMCID: PMC6173985.
4. He X,Zeng H, Chen ST, Roman RJ, Aschner JL, Didion S, Chen Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction. J Mol Cell Cardiol. 2017 Nov;112:104-113. doi: 10.1016/j.yjmcc.2017.09.007. Epub 2017 Sep 19. PubMed PMID: 28935506; PubMed Central PMCID: PMC5647246
5. He X,Zeng H, Chen Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease. J Cell Physiol. 2019 Mar;234(3):2252-2265. doi: 10.1002/jcp.27200. Epub 2018 Aug 21. Review. PubMed PMID: 30132870; PubMed Central PMCID: PMC6275096.
6. Li L, Zeng H, He X,Chen Sirtuin 3 Alleviates Diabetic Cardiomyopathy by Regulating TIGAR and Cardiomyocyte Metabolism. J Am Heart Assoc. 2021 Feb;10(5):e018913. doi: 10.1161/JAHA.120.018913. Epub 2021 Feb 15. PubMed PMID: 33586458; PubMed Central PMCID: PMC8174281.
7. Su H, Zeng H, He X,Zhu SH, Chen Histone Acetyltransferase p300 Inhibitor Improves Coronary Flow Reserve in SIRT3 (Sirtuin 3) Knockout Mice. J Am Heart Assoc. 2020 Sep 15;9(18):e017176. doi: 10.1161/JAHA.120.017176. Epub 2020 Aug 31. PubMed PMID: 32865093.
8. Zeng H, He X,Chen JX. Endothelial Sirtuin 3 Dictates Glucose Transport to Cardiomyocyte and Sensitizes Pressure Overload-Induced Heart Failure. J Am Heart Assoc. 2020 Jun 2;9(11):e015895. doi: 10.1161/JAHA.120.015895. Epub 2020 May PubMed PMID: 32468895.
9. Zeng H, He X,Chen A Sex-Specific Role of Endothelial Sirtuin 3 on Blood Pressure and Diastolic Dysfunction in Female Mice. Int J Mol Sci. 2020 Dec 21;21(24). doi: 10.3390/ijms21249744. PubMed PMID: 33371209; PubMed Central PMCID: PMC7766145.
10. Wang S, Zeng H, Xie XJ, Tao YK, He X,Roman RJ, Aschner JL, Chen Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling. Oncotarget. 2016 Sep 13;7(37):58848-58861. doi: 10.18632/oncotarget.11585. PubMed PMID: 27613846.
11. Wang S, Zeng H, Chen S, Zhou LY, Xie XJ, He X,Tao YK, Tuo QH, Deng CQ, Liao DF, Chen, Ablation of endothelial prolyl hydroxylase domain protein-2 promotes renal vascular remodeling and fibrosis in mice. J. Cell. Mol. Med. 2017 Sep;21(9):1967-1978. doi: 10.1111/jcmm.13117. Epub 2017 Mar 7. PubMed PMID: 28266128; PubMed Central PMCID: PMC5571552.
12. Tao YK, Zeng H, Zhang GQ, Chen S, Xie XJ, He X,Wang S, Wen HY, Chen JX. Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia. Int J Cardiol. 2017 Jun 1;236:413-422. doi: 10.1016/j.ijcard.2017.01.096. Epub 2017 Jan 24. PubMed PMID: 28131704; PubMed Central PMCID: PMC5639707.

C3. Mechanism of exacerbated acute heart injury and impaired recovery post-myocardial ischemia.My initial work in my graduate training under the supervision of Dr. Chen focused on the role of SIRT3 in coronary microvascular function and post-myocardial ischemia recovery. SIRT3, a major nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase in mitochondria, declines with aging and its ablation is associated with accelerated development of cardiovascular diseases. The goal of the study was to investigate whether ablation of SIRT3 causes coronary microvascular dysfunction, exacerbates post-myocardial ischemia (MI) cardiac dysfunction and impairs cardiac recovery. We found that SIRT3 knockout (KO) mice presented a pre- existing coronary microvascular dysfunction and microvascular rarefaction, accompanied by loss of capillary- pericytes in the heart and reduced angiogenic capabilities in SIRT3 deficient endothelial cells (EC). SIRT3 KO mice subjected to myocardial ischemia by the ligation of left anterior descending coronary artery (LAD) exhibited more severe cardiac dysfunction together with decreased pericyte/EC coverage than that of wild type (WT) mice. In contrast, overexpression of SIRT3 preserved cardiac function in post-MI mice. Our recent work suggests a potential mechanism by which SIRT3 deletion exacerbates post-MI cardiac dysfunction and impairment of cardiac recovery involving microvascular rarefaction and pre-existing coronary microvascular dysfunction.

1. He X,Zeng H, Chen JX. Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial Int J Cardiol. 2016 Jul 15;215:349-57. doi: 10.1016/j.ijcard.2016.04.092. PubMed PMID: 27128560.
2. Zeng H, Vaka VR, He X,Booz GW, Chen JX. High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss. J Cell Mol Med. (2015) Mar 17. PubMed PMID:
3. Hou X, Zeng H, He X,Chen JX. Sirt3 is essential for apelin-induced angiogenesis in post-myocardial infarction of diabetes. J Cell Mol Med. 2014 Oct 14. PubMed PMID: 25311234.
4. Zeng H, He X,Hou X, Li L, Chen JX. Apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3. Am J Physiol Heart Circ Physiol. 2014 Feb 15;306(4):H585-97. PubMed PMID: 24363305.
5. Li L, Zeng H, Hou X, He X,Chen JX. Myocardial injection of apelin-overexpressing bone marrow cells improves cardiac repair via upregulation of Sirt3 after myocardial infarction. PLoS One. 2013 Sep 6;8(9):e71041. PubMed PMID:
6. Zeng H, He X, Tuo QH, Liao DF, Zhang GQ, Chen JX. LPS causes pericyte loss and microvascular dysfunction via disruption of Sirt3/angiopoietins/Tie-2 and HIF-2α/Notch3 pathways. Sci Rep. 2016 Feb 12;6:20931. PubMed PMID: 26868537.

C4. Mechanisms of renal injury in aging, diabetes, and hypertension.I have done study on renal ischemia- reperfusion injury in aging and diabetes, demonstrating that elderly T2DN rats with diabetic nephropathy are more susceptible to renal IR injury than diabetic animals with mild injury or age-matched control animals. We have mapped the Dusp5 gene in a small region of chromosome 1 in FHH rats that alter autoregulation of renal blood flow and contribute to the development of renal vascular diseases. I was also involved in developing a modified technique to fill the renal vasculature with a silicon rubber (Microfil) compound and obtain morphologic information about the intrarenal distribution of capillary blood flow under a variety of conditions. The advantage of the technique is that it provides anatomical information regarding the number, diameter and branching patterns of capillaries in the postglomerular circulation critical in determining the mechanisms involved in the redistribution of blood flow in the kidney. We found that a mutation of γ-Adducin impairs autoregulation of renal blood flow and promotes the development of kidney disease. I also have experience in a hypertensive swine model that renovascular hypertension is induced by implantation of a local irritant coil inside the main renal artery, unilaterally or bilaterally, leading to renal artery stenosis, hypertension, and progressive deterioration of renal function and development of renal injury. I was involved in the studies of a single-kidney hemodynamics and function in vivo using high-resolution clinically-validated multi-detector computerized tomography and studies of the renal microvascular architecture in situ using 3D micro-computerized tomography. I also performed renal histology, morphometric analyses, and immunohistochemistry for studying underlying mechanisms of target organ injury in renovascular and chronic renal disease and responses to treatments.

1. He X,Cantrell AC, Williams QA, Chen JX, Zeng TIGAR deficiency sensitizes angiotensin-II-induced renal fibrosis and glomerular injury. Physiol Rep. 2022 Apr;10(8):e15234. doi: 10.14814/phy2.15234. PubMed PMID: 35441828.
2. Feng X, Su H, He X,Chen JX, Zeng H. SIRT3 Deficiency Sensitizes Angiotensin-II-Induced Renal Fibrosis. Cells. 2020 Nov 20;9(11). doi: 10.3390/cells9112510. PubMed PMID: 33233553; PubMed Central PMCID: PMC7699810.
3. Zhao Y, Zeng H, Liu B, He X,Chen JX. Endothelial prolyl hydroxylase 2 is necessary for angiotensin II- mediated renal fibrosis and injury. Am J Physiol Renal Physiol. 2020 Aug 1;319(2):F345-F357. doi: 10.1152/ajprenal.00032.2020. Epub 2020 Jul 27. PubMed PMID: 32715763; PubMed Central PMCID: PMC7473903.
4. Fan F, Geurts AM, Pabbidi MR, Ge Y, Zhang C, Wang S, Liu Y, Gao W, Guo Y, Li L, He X,Lv W, Muroya Y, Hirata T, Prokop J, Booz GW, Jacob HJ, Roman A Mutation in γ-Adducin Impairs Autoregulation of Renal Blood Flow and Promotes the Development of Kidney Disease. J Am Soc Nephrol. 2020 Apr;31(4):687-700. doi: 10.1681/ASN.2019080784. Epub 2020 Feb 6. PubMed PMID: 32029431; PubMed Central PMCID: PMC7191921.
5. Zhang C, He X,Murphy SR, Zhang H, Wang S, Ge Y, Gao W, Williams JM, Geurts AM, Roman RJ, Fan Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury. J Pharmacol Exp Ther. 2019 Aug;370(2):206-217. doi: 10.1124/jpet.119.258954. Epub 2019 May PubMed PMID: 31118214; PubMed Central PMCID: PMC6636243.
6. Muroya Y, He X,Fan L, Wang S, Xu R, Fan F, Roman RJ. Enhanced renal ischemia-reperfusion injury in aging and diabetes. Am J Physiol Renal Physiol. 2018 Dec 1;315(6):F1843-F1854. doi: 10.1152/ajprenal.00184.2018. Epub 2018 Sep 12. PubMed PMID: 30207168; PubMed Central PMCID: PMC6336981.
7. Fan L, Wang S, He X, Gonzalez-Fernandez E, Lechene C, Fan F, Roman RJ. Visualization of the intrarenal distribution of capillary blood flow. Physiol Rep. 2019 Apr;7(8):e14065. doi: 10.14814/phy2.14065. PubMed PMID: 31008571; PubMed Central PMCID:
8. Kelsen S*, He X*,Chade AR. Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney. Am J Physiol Renal Physiol. 2012 Aug 15;303(4):F576-83. doi: 10.1152/ajprenal.00154.2012. Epub 2012 May 23. PubMed PMID: 22622460; PubMed Central PMCID: *Co-first author.
9. Fan F, Geurts AM, Pabbidi MR, Ge Y, Zhang C, Wang S, Liu Y, Gao W, Guo Y, Li L, He X,Lv W, Muroya Y, Hirata T, Prokop J, Booz GW, Jacob HJ, Roman RJ. A Mutation in γ-Adducin Impairs Autoregulation of Renal Blood Flow and Promotes the Development of Kidney Disease. J Am Soc Nephrol. 2020 Apr;31(4):687-700. doi: 10.1681/ASN.2019080784. Epub 2020 Feb 6. PubMed PMID: 32029431; PubMed Central PMCID: PMC7191921.

Complete List of Published Work in My Bibliography:

https://www.ncbi.nlm.nih.gov/myncbi/1NE-hQoJryl/bibliography/public/

Additional Information: Research Support and/or Scholastic Performance

American Heart Association Postdoctoral Fellowship. January 1, 2023-December 31, 2024. “Effect of cell specific PD-1 inhibition on cardiac toxicity.” Role: PI