Hua Linda Cai, M.D., Ph.D.

Mailing Address:
UCLA Department of Anesthesiology
757 Westwood Plaza, Suite 3325
Los Angeles, CA 90095

Work Address:
650 Charles E Young Dr, South
Los Angeles, CA 90095

Professor, Anesthesiology
Member, Molecular Medicine, Cell & Developmental Biology GPB Home Area, JCCC Signal Transduction and Therapeutics Program Area, Molecular Pharmacology GPB Home Area, Molecular, Cellular & Integrative Physiology GPB Home Area
Faculty, Medicine, Cardiovascular Research Lab
Research Interests
The Cai laboratory has long-term interests in molecular regulation of the cardiovascular protective enyzme endothelial nitric oxide synthase (eNOS), and contributions to cardiovascular diseases of increased reactive oxygen species production (ROS). ROS are a family of oxygen-derived molecules that are highly reactive to directly cause protein or DNA damage, or activate signal transduction pathways that are essential in disease initiation or progression. For example, one electron reduction of molecular oxygen results in formation of superoxide anion, which can ultra rapidly react with nitric oxide to result in formation of a more toxic oxidant peroxynitrite, and a loss in nitric oxide bioavailability and nitric oxide-dependent vasodilatation, as well as nitric oxide-dependent anti-inflammatory and anti-atherosclerotic functions. The goal of our research is to delineate details of eNOS regulation under oxidant stress environment, which may lead to novel therapeutics targeting an array of cardiovascular disorders including hypertension, atherosclerosis, diabetic vascular diseases, heart failure and biological process of aging. In deed, in the past few years our lab has discovered and characterized novel mechanisms whereby eNOS is dysfunctionally regulated to generate ROS itself, deteriorating oxidant stress [Proc Natl Acad Sci U S A. Track II (2005) 102(25):9056-61; Diabetes (2007) Jan 56(1):118-126; Am. J. Physiol. Heart Circ. Physiol. (2009) Jul;297(1):H331-9; J. Mol Cell Cardiol. (2009)]. Based on these findings are currently testing novel therapeutics in mouse models of hypertension and diabetes. These regiments are anticipated to restore eNOS function to hinder disease progression. Another major direction of research in our laboratory is to identify innovative pathways of vascular repair. Endothelium is the thin lay of endothelial cells lining the luminal surface of blood vessels. It represents the first line of defense protecting the blood vessels against blood-borne insults such as hormones (i.e. elevated angiotensin II in hypertensive patients), disturbed flow and inflammatory cytokines (released by inflammatory cells). Additionally, endothelium can be physically damaged during catheterization or endovascular surgeries. Without intact endothelium, the rest of the blood vessels can be damaged to cause severe vascular disorders. Thus our goal has been to identify and characterize novel vascular repair mechanisms that can lead to enhanced endothelial cell proliferation and migration, as well as accelerated wound closure. Some of the findings have been published in prestigious journals [Proc Natl Acad Sci U S A. (2006) Track II, Apr 25;103(17):6530-5; Circulation Research (2009);104:50-59] Our group is also interested in novel pathways mediating nitric oxide-dependent cardioprotection. We have recently shown that netrin-1 potently protects the heart from ischemia/reperfusion induced myocardial infarction via activation of DCC/NO/ERK1/2/eNOS/DCC feed-forward mechanism [J. Mol Cell Cardiol. (2010)]. We have projects ongoing to also investigate oxidant stress mechanisms in human atrial fibrillation, the most common cardiac arrhythmia; a role of vascular oxidative stress in obesity; and novel therapeutics eliminating cardiovascular side effects of cancer drugs.

A selected list of publications:

Oak, J. H. Cai, H.   Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice, Diabetes, 2007; 56(1): 118-26..
Cai, H.   A new mechanism for flow-mediated vasoprotection? Focus on "lung endothelial cell proliferation with decreased shear stress is mediated by reactive oxygen species", Am J Physiol Cell Physiol, 2006; 290(1): C35-6.
Nguyen, A. Cai, H.   Netrin-1 induces angiogenesis via a DCC-dependent ERK1/2-eNOS feed-forward mechanism, Proc Natl Acad Sci U S A, 2006; 103(17): 6530-5. Epub 2006 Apr 12..
Chalupsky, K. Cai, H.   Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase, Proc Natl Acad Sci U S A, 2005; 102(25): 9056-61. Epub 2005 Jun 7..
Laude, K. Cai, H. Fink, B. Hoch, N. Weber, D. S. McCann, L. Kojda, G. Fukai, T. Schmidt, H. H. Dikalov, S. Ramasamy, S. Gamez, G. Griendling, K. K. Harrison, D. G.   Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice, Am J Physiol Heart Circ Physiol, 2005; 288(1): H7-H12. Epub 2004 Oct 07..
Cai, H.   Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences, Cardiovasc Res, 2005; 68(1): 26-36.
Cai, H.   NAD(P)H oxidase-dependent self-propagation of hydrogen peroxide and vascular disease, Circ Res, 2005; 96(8): 818-22..
McNally, J. S. Saxena, A. Cai, H. Dikalov, S. Harrison, D. G.   Regulation of xanthine oxidoreductase protein expression by hydrogen peroxide and calcium, Arterioscler Thromb Vasc Biol, 2005; 25(8): 1623-8. Epub 2005 May 19..
Lade, K. Cai, H. Fink, B. Hoch, N. Weber, D. S. McCann, L. Kojda, G. Fukai, T. Dikalov, S. Ramasamy, S. Gamez, G. Griendling, K. Harrison, D.   Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice, Am J Physiol, 2004; In-press: .
Cai, H. McNally, J. S. Weber, M. Harrison, D.G.   Oscillatory shear stress upregulation of endothelial nitric oxide synthase requires intracellular hydrogen peroxide and CaMKII, J Mol Cell Cardiol, 2004; 37(1): 121-5.
Nguyen, A. Chen, P. Cai, H.   Role of CaMKII in hydrogen peroxide activation of ERK1/2, p38 MAPK, HSP27 and actin reorganization in endothelial cells, FEBS Lett, 2004; 572(1-3): 307-13..
Cai, H. Li, Z. Davis, M. E. Kanner, W. Harrison, D. G. Dudley, S. C., Jr.   Akt-dependent phosphorylation of serine 1179 and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 cooperatively mediate activation of the endothelial nitric-oxide synthase by hydrogen peroxide, Mol Pharmacol, 2003; 63(2): 325-31..
Harrison, D. G. Cai, H. Landmesser, U. Griendling, K. K.   Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease J Renin Angiotensin Aldosterone Syst, 2003; 4(2): 51-61.
Davis, M. E. Cai, H. McCann, L. Fukai, T. Harrison, D. G.   Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training, Am J Physiol Heart Circ Physiol, 2003; 284(4): H1449-53..
Alp, N. J. Mussa, S. Khoo, J. Cai, S. Guzik, T. Jefferson, A. Goh, N. Rockett, K. A. Channon, K. M.   Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression, J Clin Invest, 2003; 112(5): 725-35..
Cai, H. Griendling, K. K. Harrison, D. G.   The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases, Trends Pharmacol Sci, 2003; 24(9): 471-8..
Cai, H. Li, Z. Goette, A. Mera, F. Honeycutt, C. Feterik, K. Wilcox, J. N. Dudley, S. C., Jr. Harrison, D. G. Langberg, J. J.   Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke, Circulation, 2002; 106(22): 2854-8..
Cai, H. Li, Z. Dikalov, S. Holland, S. M. Hwang, J. Jo, H. Dudley, S. C., Jr. Harrison, D. G.   NAD(P)H oxidase-derived hydrogen peroxide mediates endothelial nitric oxide production in response to angiotensin II, J Biol Chem, 2002; 277(50): 48311-7..
Landmesser, U. Cai, H. Dikalov, S. McCann, L. Hwang, J. Jo, H. Holland, S. M. Harrison, D. G.   Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II, Hypertension, 2002; 40(4): 511-5..
Cai, H. Davis, M. E. Drummond, G. R. Harrison, D. G.   Induction of endothelial NO synthase by hydrogen peroxide via a Ca(2+)/calmodulin-dependent protein kinase II/janus kinase 2-dependent pathway, Arterioscler Thromb Vasc Biol, 2001; 21(10): 1571-6..
Davis, M. E. Cai, H. Drummond, G. R. Harrison, D. G.   Shear stress regulates endothelial nitric oxide synthase expression through c-Src by divergent signaling pathways, Circ Res, 2001; 89(11): 1073-80..
Cai, H. Harrison, D. G.   Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress, Circ Res, 2000; 87(10): 840-4..
Drummond, G. R. Cai, H. Davis, M. E. Ramasamy, S. Harrison, D. G.   Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide, Circ Res, 2000; 86(3): 347-54.
Gao Ling, Chalupsky Karel, Stefani Enrico, Cai Hua   Mechanistic insights into folic acid-dependent vascular protection: dihydrofolate reductase (DHFR)-mediated reduction in oxidant stress in endothelial cells and angiotensin II-infused mice: a novel HPLC-based fluorescent assay for DHFR activity Journal of molecular and cellular cardiology, 2009; 47(6): 752-60.
Bouhidel Jalaleddinne Omar, Wang Ping, Siu Kin Lung, Li Hong, Youn Ji Youn, Cai Hua   Netrin-1 improves post-injury cardiac function in vivo via DCC/NO-dependent preservation of mitochondrial integrity, while attenuating autophagy Biochimica et biophysica acta, 2015; 1852(2): 277-89.
Gao Ling, Pung Yuh-Fen, Zhang Jun, Chen Peng, Wang Ting, Li Min, Meza Miguel, Toro Ligia, Cai Hua   Sepiapterin reductase regulation of endothelial tetrahydrobiopterin and nitric oxide bioavailability American journal of physiology. Heart and circulatory physiology, 2009; 297(1): H331-9.
Li Qiang, Wang Ping, Ye Keqiang, Cai Hua   Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO Proceedings of the National Academy of Sciences of the United States of America, 2015; 112(3): 899-904.
Zhang Yixuan, Cai Hua   Editorial commentary: Endothelial-to-mesenchymal transition: When the good one goes bad Trends in cardiovascular medicine, 2017; 27(6): 394-396.
Lu Gang, Sun Haipeng, She Pengxiang, Youn Ji-Youn, Warburton Sarah, Ping Peipei, Vondriska Thomas M, Cai Hua, Lynch Christopher J, Wang Yibin   Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells The Journal of clinical investigation, 2009; 119(6): 1678-87.
Siu Kin Lung, Cai Hua   Circulating tetrahydrobiopterin as a novel biomarker for abdominal aortic aneurysm American journal of physiology. Heart and circulatory physiology, 2014; 307(11): H1559-64.
Siu Kin Lung, Lotz Christopher, Ping Peipei, Cai Hua   Netrin-1 abrogates ischemia/reperfusion-induced cardiac mitochondrial dysfunction via nitric oxide-dependent attenuation of NOX4 activation and recoupling of NOS Journal of molecular and cellular cardiology, 2015; 78(3): 174-85.
Youn Ji-Youn, Wang Ting, Cai Hua   An ezrin/calpain/PI3K/AMPK/eNOSs1179 signaling cascade mediating VEGF-dependent endothelial nitric oxide production Circulation research, 2009; 104(1): 50-9.
Zhang Yixuan, Shimizu Hirohito, Siu Kin Lung, Mahajan Aman, Chen Jau-Nian, Cai Hua   NADPH oxidase 4 induces cardiac arrhythmic phenotype in zebrafish The Journal of biological chemistry, 2014; 289(33): 23200-8.
Gao Ling, Laude Karine, Cai Hua   Mitochondrial pathophysiology, reactive oxygen species, and cardiovascular diseases The Veterinary clinics of North America. Small animal practice, 2008; 38(1): 137-55, vi.
Cai Hua, Liu Depei, Garcia Joe G N   CaM Kinase II-dependent pathophysiological signalling in endothelial cells Cardiovascular research, 2008; 77(1): 30-4.
Youn Ji-Youn, Siu Kin Lung, Lob Heinrich E, Itani Hana, Harrison David G, Cai Hua   Role of vascular oxidative stress in obesity and metabolic syndrome Diabetes, 2014; 63(7): 2344-55.
Cai Hua, Dikalov Sergey, Griendling Kathy K, Harrison David G   Detection of reactive oxygen species and nitric oxide in vascular cells and tissues: comparison of sensitivity and specificity Methods in molecular medicine, 2007; 139(1): 293-311.
Siu Kin Lung, Miao Xiao Niu, Cai Hua   Recoupling of eNOS with folic acid prevents abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E null mice PloS one, 2014; 9(2): e88899.
Siu Kin Lung, Li Qiang, Zhang Yixuan, Guo Jun, Youn Ji Youn, Du Jie, Cai Hua   NOX isoforms in the development of abdominal aortic aneurysm Redox biology, 2017; 11(6): 118-125.
Bouhidel Jalaleddinne Omar, Wang Ping, Li Qiang, Cai Hua   Pharmacological postconditioning treatment of myocardial infarction with netrin-1 Frontiers in bioscience (Landmark edition), 2014; 19(2): 566-70.
Liu Norika Mengchia, Siu Kin Lung, Youn Ji Youn, Cai Hua   Attenuation of neointimal formation with netrin-1 and netrin-1 preconditioned endothelial progenitor cells Journal of molecular medicine (Berlin, Germany), 2017; 95(3): 335-348.
Youn Ji-Youn, Zhang Jun, Zhang Yixuan, Chen Houzao, Liu Depei, Ping Peipei, Weiss James N, Cai Hua   Oxidative stress in atrial fibrillation: an emerging role of NADPH oxidase Journal of molecular and cellular cardiology, 2013; 62(2): 72-9.
Zhang Yixuan, Li Qiang, Youn Ji Youn, Cai Hua   Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells: IMPLICATIONS IN VEGF-DEPENDENT ANGIOGENESIS AND DIABETIC WOUND HEALING The Journal of biological chemistry, 2017; 292(2): 407-416.
Li Jingyuan, Iorga Andrea, Sharma Salil, Youn Ji-Youn, Partow-Navid Rod, Umar Soban, Cai Hua, Rahman Siamak, Eghbali Mansoureh   Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion injury more efficiently than cyclosporine-A Anesthesiology, 2012; 117(4): 836-46.
Sun Haipeng, Olson Kristine C, Gao Chen, Prosdocimo Domenick A, Zhou Meiyi, Wang Zhihua, Jeyaraj Darwin, Youn Ji-Youn, Ren Shuxun, Liu Yunxia, Rau Christoph D, Shah Svati, Ilkayeva Olga, Gui Wen-Jun, William Noelle S, Wynn R Max, Newgard Christopher B, Cai Hua, Xiao Xinshu, Chuang David T, Schulze Paul Christian, Lynch Christopher, Jain Mukesh K, Wang Yibin   Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure Circulation, 2016; 133(21): 2038-49.
Youn Ji-Youn, Nguyen Andrew, Cai Hua   Inhibition of XO or NOX attenuates diethylstilbestrol-induced endothelial nitric oxide deficiency without affecting its effects on LNCaP cell invasion and apoptosis Clinical science (London, England : 1979), 2012; 123(8): 509-18.
Siu Kin Lung, Gao Ling, Cai Hua   Differential Roles of Protein Complexes NOX1-NOXO1 and NOX2-p47phox in Mediating Endothelial Redox Responses to Oscillatory and Unidirectional Laminar Shear Stress The Journal of biological chemistry, 2016; 291(16): 8653-62.
Li Qiang, Youn Ji-Youn, Li Shan, Cai Hua   Reply: To PMID 25882860 Journal of hypertension, 2015; 33(11): 2368-70.
Li Jingyuan, Umar Soban, Iorga Andrea, Youn Ji-Youn, Wang Yibin, Regitz-Zagrosek Vera, Cai Hua, Eghbali Mansoureh   Cardiac vulnerability to ischemia/reperfusion injury drastically increases in late pregnancy Basic research in cardiology, 2012; 107(4): 271.
Miao Xiao Niu, Siu Kin Lung, Cai Hua   Nifedipine attenuation of abdominal aortic aneurysm in hypertensive and non-hypertensive mice: Mechanisms and implications Journal of molecular and cellular cardiology, 2015; 87(11): 152-9.
Youn Ji Youn, Wang Ting, Blair John, Laude Karine M, Oak Jeong-Ho, McCann Louise A, Harrison David G, Cai Hua   Endothelium-specific sepiapterin reductase deficiency in DOCA-salt hypertension American journal of physiology. Heart and circulatory physiology, 2012; 302(11): H2243-9.
Zhang Jun, Youn Ji Youn, Kim Antony Y, Ramirez Rafael J, Gao Ling, Ngo Doan, Chen Peng, Scovotti Jennifer, Mahajan Aman, Cai Hua   NOX4-Dependent Hydrogen Peroxide Overproduction in Human Atrial Fibrillation and HL-1 Atrial Cells: Relationship to Hypertension Frontiers in physiology, 2012; 3(4): 140.
Youn Ji-Youn, Zhou Jun, Cai Hua   Bone Morphogenic Protein 4 Mediates NOX1-Dependent eNOS Uncoupling, Endothelial Dysfunction, and COX2 Induction in Type 2 Diabetes Mellitus Molecular endocrinology (Baltimore, Md.), 2015; 29(8): 1123-33.
Zhang Jun, Lin Amanda, Powers Jared, Lam Maggie P, Lotz Christopher, Liem David, Lau Edward, Wang Ding, Deng Ning, Korge Paavo, Zong Nobel C, Cai Hua, Weiss James, Ping Peipei   Perspectives on: SGP symposium on mitochondrial physiology and medicine: mitochondrial proteome design: from molecular identity to pathophysiological regulation The Journal of general physiology, 2012; 139(6): 395-406.
Li Qiang, Cai Hua   Induction of cardioprotection by small netrin-1-derived peptides American journal of physiology. Cell physiology, 2015; 309(2): C100-6.
Gao Ling, Siu Kin L, Chalupsky Karel, Nguyen Andrew, Chen Peng, Weintraub Neal L, Galis Zorina, Cai Hua   Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: treatment with folic acid Hypertension (Dallas, Tex. : 1979), 2012; 59(1): 158-66.
Li Qiang, Youn Ji-Youn, Cai Hua   Mechanisms and consequences of endothelial nitric oxide synthase dysfunction in hypertension Journal of hypertension, 2015; 33(6): 1128-36.
Zhang Jun, Cai Hua   Netrin-1 prevents ischemia/reperfusion-induced myocardial infarction via a DCC/ERK1/2/eNOS s1177/NO/DCC feed-forward mechanism Journal of molecular and cellular cardiology, 2010; 48(6): 1060-70.
Li Qiang, Cai Hua   ANO1 taking center stage: blood pressure regulation in SHRs Journal of molecular and cellular cardiology, 2015; 82(6): 216-7.
Oak Jeong-Ho, Youn Ji-Youn, Cai Hua   Aminoguanidine inhibits aortic hydrogen peroxide production, VSMC NOX activity and hypercontractility in diabetic mice Cardiovascular diabetology, 2009; 8(6): 65.
Youn Ji Youn, Cai Hua   Fueling up skeletal muscle to reduce obesity: A TrkB story Chemistry & biology, 2015; 22(3): 311-2.
Zhang YX, Liu NM, Wang YC, Youn JY, Cai H   Endothelial cell calpain as a critical modulator of angiogenesis, Biochim Biophys Acta. Mol. Basis of Dis. , 2017; 1863(6): 1326-1335.
Cai H, Wang C   Graphical review: The redox dark side of e-cigarettes; exposure to oxidants and public health concerns, Redox Biol, 2017; 13: 402-406.
Cai H, Wang C   Surviving With Smog and Smoke: Precision Interventions?, Chest, 2017; 152(5): 925-929, "Ahead of the Curve" Collection.
Cheng Y, Yuan Q, Vergnes L, Rong X, Youn JY, Li J, Yu Y, Liu W, Cai H, Lin J, Tontonoz P, Hong C, Reue K, Wang CY   KDM4B protects against obesity and metabolic dysfunction, Proc. Natl. Acad. Sci. U. S. A. , 2018; 115(24): E5566-E5575.
Li H*, Li Q*, Zhang Y, Liu W, Gu B, Narumi T, Siu KL, Youn JY, Liu P, Yang X, Cai H   Novel treatment of hypertension by specifically targeting E2F for the restoration of dihydrofolate reductase and eNOS function under oxidative stress, Hypertension, 2019; 73(1): 179-189, “High Impact Paper in Hypertension” collection.
Li Q, Youn JY, Siu KL, Murugesan P, Zhang Y, Cai H.   Knockout of dihydrofolate reductase in mice induces abdominal aortic aneurysm and hypertension via mitochondrial dysfunction, Redox Biology, 2019; Mar 29;24: 101185.
Zhang Y, Murugesan P, Huang K, Cai H   NADPH oxiase-dependent oxidase crosstalks in cardiovascular diseases: Targets of novel therapies, Nature Reviews Cardiology, 2019; In press: .