Professor, Anesthesiology, University of California Los Angeles
Professor, Medicine, University of California Los Angeles
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
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.
- Youn JY, Zhang Y, Wu Y, Cannesson M, Cai H. Therapeutic application of estrogen for COVID-19: Attenuation of SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation, ROS production and MCP-1 upregulation in endothelial cells.. Redox biology, 2021.
- Huang K, Narumi T, Zhang Y, Li Q, Murugesan P, Wu Y, Liu NM, Cai H. Targeting MicroRNA-192-5p, a Downstream Effector of NOXs (NADPH Oxidases), Reverses Endothelial DHFR (Dihydrofolate Reductase) Deficiency to Attenuate Abdominal Aortic Aneurysm Formation.. Hypertension (Dallas, Tex. : 1979), 2021.
- Guo Z, Zhang Y, Liu C, Youn JY, Cai H. Toll-Like Receptor 2 (TLR2) Knockout Abrogates Diabetic and Obese Phenotypes While Restoring Endothelial Function via Inhibition of NOX1.. Diabetes, 2021.
- Zhang Y, Wang L, Mutlu GM, Cai H. More to Explore: Further Definition of Risk Factors for COPD - Differential Gender Difference, Modest Elevation in PM2.5, and e-Cigarette Use.. Frontiers in physiology, 2021.
- Huang K, Zhang P, Zhang Z, Youn JY, Wang C, Zhang H, Cai H. Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms.. Pharmacology & therapeutics, 2021.
- Huang K, Wang Y, Siu KL, Zhang Y, Cai H. Targeting feed-forward signaling of TGFβ/NOX4/DHFR/eNOS uncoupling/TGFβ axis with anti-TGFβ and folic acid attenuates formation of aortic aneurysms: Novel mechanisms and therapeutics.. Redox biology, 2020.
- Cai H, Garcia JGN, Wang C. More to Add to E-Cigarette Regulations: Unified Approaches.. Chest, 2020.
- Cai H. Sex difference and smoking predisposition in patients with COVID-19.. The Lancet. Respiratory medicine, 2020.
- Li Q, Youn JY, Siu KL, Murugesan P, Zhang Y, Cai H. Knockout of dihydrofolate reductase in mice induces hypertension and abdominal aortic aneurysm via mitochondrial dysfunction.. Redox biology, 2019.
- 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 Restoration of Endothelial Dihydrofolate Reductase and eNOS Function Under Oxidative Stress.. Hypertension (Dallas, Tex. : 1979), 2019.
- Cheng Y, Yuan Q, Vergnes L, Rong X, Youn JY, Li J, Yu Y, Liu W, Cai H, Lin JD, Tontonoz P, Hong C, Reue K, Wang CY. KDM4B protects against obesity and metabolic dysfunction.. Proceedings of the National Academy of Sciences of the United States of America, 2018.
- Cai H, Wang C. Surviving With Smog and Smoke: Precision Interventions?. Chest, 2017.
- Cai H, Wang C. Graphical review: The redox dark side of e-cigarettes; exposure to oxidants and public health concerns.. Redox biology, 2017.
- Zhang Y, Cai H. Editorial commentary: Endothelial-to-mesenchymal transition: When the good one goes bad.. Trends in cardiovascular medicine, 2017.
- Zhang Y, Liu NM, Wang Y, Youn JY, Cai H. Endothelial cell calpain as a critical modulator of angiogenesis.. Biochimica et biophysica acta. Molecular basis of disease, 2017.
- Liu NM, Siu KL, Youn JY, Cai H. Attenuation of neointimal formation with netrin-1 and netrin-1 preconditioned endothelial progenitor cells.. Journal of molecular medicine (Berlin, Germany), 2016.
- Zhang Y, Li Q, Youn JY, Cai H. 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, 2016.
- Siu KL, Li Q, Zhang Y, Guo J, Youn JY, Du J, Cai H. NOX isoforms in the development of abdominal aortic aneurysm.. Redox biology, 2016.
- Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn JY, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui WJ, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y. Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.. Circulation, 2016.
- Siu KL, Gao L, Cai H. 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.
- Li Q, Youn JY, Li S, Cai H. Reply: To PMID 25882860.. Journal of hypertension, 2015.
- Miao XN, Siu KL, Cai H. Nifedipine attenuation of abdominal aortic aneurysm in hypertensive and non-hypertensive mice: Mechanisms and implications.. Journal of molecular and cellular cardiology, 2015.
- Ping P, Gustafsson ÅB, Bers DM, Blatter LA, Cai H, Jahangir A, Kelly D, Muoio D, O'Rourke B, Rabinovitch P, Trayanova N, Van Eyk J, Weiss JN, Wong R, Schwartz Longacre L. Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative.. Circulation research, 2015.
- Youn JY, Zhou J, Cai H. Bone Morphogenic Protein 4 Mediates NOX1-Dependent eNOS Uncoupling, Endothelial Dysfunction, and COX2 Induction in Type 2 Diabetes Mellitus.. Molecular endocrinology (Baltimore, Md.), 2015.
- Li Q, Youn JY, Cai H. Mechanisms and consequences of endothelial nitric oxide synthase dysfunction in hypertension.. Journal of hypertension, 2015.
- Li Q, Cai H. Induction of cardioprotection by small netrin-1-derived peptides.. American journal of physiology. Cell physiology, 2015.
- Li Q, Cai H. ANO1 taking center stage: blood pressure regulation in SHRs.. Journal of molecular and cellular cardiology, 2015.
- Youn JY, Cai H. Fueling up skeletal muscle to reduce obesity: A TrkB story.. Chemistry & biology, 2015.
- Li Q, Wang P, Ye K, Cai H. 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.
- Siu KL, Cai H. Circulating tetrahydrobiopterin as a novel biomarker for abdominal aortic aneurysm.. American journal of physiology. Heart and circulatory physiology, 2014.
- Siu KL, Lotz C, Ping P, Cai H. 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, 2014.
- Zhang Y, Shimizu H, Siu KL, Mahajan A, Chen JN, Cai H. NADPH oxidase 4 induces cardiac arrhythmic phenotype in zebrafish.. The Journal of biological chemistry, 2014.
- Bouhidel JO, Wang P, Siu KL, Li H, Youn JY, Cai H. Netrin-1 improves post-injury cardiac function in vivo via DCC/NO-dependent preservation of mitochondrial integrity, while attenuating autophagy.. Biochimica et biophysica acta, 2014.
- Siu KL, Miao XN, Cai H. Recoupling of eNOS with folic acid prevents abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E null mice.. PloS one, 2014.
- Youn JY, Siu KL, Lob HE, Itani H, Harrison DG, Cai H. Role of vascular oxidative stress in obesity and metabolic syndrome.. Diabetes, 2014.
- Bouhidel JO, Wang P, Li Q, Cai H. Pharmacological postconditioning treatment of myocardial infarction with netrin-1.. Frontiers in bioscience (Landmark edition), 2014.
- Youn JY, Zhang J, Zhang Y, Chen H, Liu D, Ping P, Weiss JN, Cai H. Oxidative stress in atrial fibrillation: an emerging role of NADPH oxidase.. Journal of molecular and cellular cardiology, 2013.
- Youn JY, Nguyen A, Cai H. 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.
- Li J, Iorga A, Sharma S, Youn JY, Partow-Navid R, Umar S, Cai H, Rahman S, Eghbali M. Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion injury more efficiently than cyclosporine-A.. Anesthesiology, 2012.
- Zhang J, Youn JY, Kim AY, Ramirez RJ, Gao L, Ngo D, Chen P, Scovotti J, Mahajan A, Cai H. NOX4-Dependent Hydrogen Peroxide Overproduction in Human Atrial Fibrillation and HL-1 Atrial Cells: Relationship to Hypertension.. Frontiers in physiology, 2012.
- Zhang J, Lin A, Powers J, Lam MP, Lotz C, Liem D, Lau E, Wang D, Deng N, Korge P, Zong NC, Cai H, Weiss J, Ping P. Perspectives on: SGP symposium on mitochondrial physiology and medicine: mitochondrial proteome design: from molecular identity to pathophysiological regulation.. The Journal of general physiology, 2012.
- Li J, Umar S, Iorga A, Youn JY, Wang Y, Regitz-Zagrosek V, Cai H, Eghbali M. Cardiac vulnerability to ischemia/reperfusion injury drastically increases in late pregnancy.. Basic research in cardiology, 2012.
- Youn JY, Wang T, Blair J, Laude KM, Oak JH, McCann LA, Harrison DG, Cai H. Endothelium-specific sepiapterin reductase deficiency in DOCA-salt hypertension.. American journal of physiology. Heart and circulatory physiology, 2012.
- Gao L, Siu KL, Chalupsky K, Nguyen A, Chen P, Weintraub NL, Galis Z, Cai H. Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: treatment with folic acid.. Hypertension (Dallas, Tex. : 1979), 2011.
- Zhang J, Cai H. 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.
- Oak JH, Youn JY, Cai H. Aminoguanidine inhibits aortic hydrogen peroxide production, VSMC NOX activity and hypercontractility in diabetic mice.. Cardiovascular diabetology, 2009.
- Gao L, Chalupsky K, Stefani E, Cai H. 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.
- Lu G, Sun H, She P, Youn JY, Warburton S, Ping P, Vondriska TM, Cai H, Lynch CJ, Wang Y. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells.. The Journal of clinical investigation, 2009.
- Gao L, Pung YF, Zhang J, Chen P, Wang T, Li M, Meza M, Toro L, Cai H. Sepiapterin reductase regulation of endothelial tetrahydrobiopterin and nitric oxide bioavailability.. American journal of physiology. Heart and circulatory physiology, 2009.
- Youn JY, Wang T, Cai H. An ezrin/calpain/PI3K/AMPK/eNOSs1179 signaling cascade mediating VEGF-dependent endothelial nitric oxide production.. Circulation research, 2008.
- Gao L, Laude K, Cai H. Mitochondrial pathophysiology, reactive oxygen species, and cardiovascular diseases.. The Veterinary clinics of North America. Small animal practice, 2008.
- Cai H, Liu D, Garcia JG. CaM Kinase II-dependent pathophysiological signalling in endothelial cells.. Cardiovascular research, 2007.
- Oak JH, Cai H. Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice.. Diabetes, 2007.
- Cai H, Dikalov S, Griendling KK, Harrison DG. Detection of reactive oxygen species and nitric oxide in vascular cells and tissues: comparison of sensitivity and specificity.. Methods in molecular medicine, 2007.