Chen Biosketch

BIOGRAPHICAL SKETCH

Name: Yingjie Chen
eRA COMMONS USER NAME (credential, e.g., agency login): chenx106
POSITION TITLE: Professor
EDUCATION/TRAINING 

Personal Statement

My laboratory has had a longstanding interest in understanding the molecular mechanisms of cardiac and lung inflammation in Heart Failure (HF) development and the transition from left heart failure to right heart failure (HF progression). We are the first to demonstrate that end-stage HF causes massive lung inflammation and lung vessel remodeling. We are also the first to show that PM2.5 profoundly exacerbated HF progression and RV hypertrophy through enhancing lung inflammation, fibrosis, and vessel remodeling in mice with existing LV failure, while the same PM2.5 exposure only caused very mild lung inflammation in normal mice. We have demonstrated activated T cells and antigen presenting cells are increased in cardiac and pulmonary tissues in HF animals, and inhibition of T cell activation or induction of endogenous T regulatory cells are both effective in attenuating HF development and HF progression. We are using various global and cell specific gene deficient mouse strains to understand how T cells and Tregs regulate cardiac and lung inflammation during HF development and progression.

In addition, we have made a number of very exciting new findings regarding the essential role of DDAH1 in degrading endogenous nitric oxide synthase inhibitor ADMA and L-NMMA. We also demonstrated the important roles of iNOS, PDE5, AMPK, and ROS in heart failure development. My overall goal is to understand the poor prognosis of HF and identify new druggable targets and methods for treating or halting HF, and HF- induced lung inflammation and consequent right heart failure. I am committed to work as a potential mentor for future junior investigators at UMMC who are interested in HF research.

Positions, Scientific Appointments, and Honors

08/19-present    Professor of physiology, Department of Physiology & Biophysics, University of Mississippi Medical Center

08/19-present    Adjunct Associate Professor, Cardiovascular Division, Department of Medicine, University of Minnesota

06/12-08/19       Associate Professor with tenure, Cardiovascular Division, University of Minnesota

08/15-2019        Adjunct Professor, Cardiovascular Department of 10th Renmin’s Hospital, Tongji University

07/05-06/12       Assistant Professor (tenure track), Cardiovascular Division, University of Minnesota

01/01-6/05         Research Associate and Research Assistant professor, University of Minnesota

06/93-08/95        Associate Professor, Interim Chairman of Physiology Department, Chinese National Research Institute of Sports Science, Beijing, China

06/91-06/93         Assistant Professor, National Research Institute of Sports Science, Beijing

07/86-08/88         Neurosurgeon, Teaching Hospital, Neimonggu Medical College, China

Honors and Awards:

2012    Excellent service award of Academy of Cardiovascular Research

2008    Dr. Marvin and Hadassah Bacaner Research Award in Cardiology, University of Minnesota

2005    Lillehei Scholars, Dean's Faculty Recruit, School of Medicine, University of Minnesota

2003 Received first NIH RO1 award

2003    Scientist Development Award –National Center of American Heart Association

1991    Honorary mention of Sports Science Award of the International Olympic Committee President

1992    Distinguished Contribution Award to the 25th Chinese Olympic Games teams

Contributions to Science

Identification of the important role of lung inflammation in HF progression. We are the first to demonstrate that end-stage HF causes massive lung inflammation and lung vessel remodeling. It is well known that end-stage HF causes dramatic increase of lung weight, a condition often described as lung edema. We provided the first direct evidence that end-stage HF is associated with a massive lung leukocyte infiltration and fibrosis [Chen et al Hypertension 2012, PMC3402091]. Remarkably, in some cases, HF-induced inflammatory cell infiltration and pulmonary fibrosis/remodeling are so extensive that the lung tissue becomes as solid as liver tissue. Therefore, we proposed that end-stage HF is a severe lung disease, indicating that increasing LV contractility alone without reducing lung inflammation/damage that accompanies HF will be inadequate (or even detrimental) in treating the end-stage HF. With the conviction that inhibiting lung damage/inflammation can stop or partially reverse the progression of end-stage CHF, we have made significant efforts to identify the factors of HF-related tissue inflammation. We have demonstrated that induction of T regulatory cells is sufficient in attenuating HF progression and development [Wang et al 2016, PMC5022287]. We demonstrated that inhibition of T cell activation by CD28 KO, B7 KO or depletion and CD11c positive antigen presenting cells significantly attenuated TAC-induced cardiac and lung inflammation and HF development [Wang et al 2016b, Wang et al. 2017, PMID: 28349258]. Recently, we demonstrated that increase of lung inflammation by short term PM2.5 exposure profoundly exacerbated lung vessel remodeling, and fibrosis, as well as RV hypertrophy, while LV hypertrophy and function were unaffected in mice with existing LV failure [Yue et al. 2019, PMID: 30861460]. These striking findings demonstrate that lung inflammation can exacerbate lung and RV remodeling without directly affecting LV failure.

In addition, we showed that inhibition of IL-1b [Shang LL JMCC 2020] and reducing oxidative stress by Isolevuglandin scavenger [Shang et al. FRBM. 2019;141:291-298, PMID: 31254620] can attenuate HF progression in mice with existing LV failure. We also demonstrated that PKR, a factor regulating inflammation, contributes to HF development independent to its expression in leukocytes [Wang et al 2014, PMC3972332]. We demonstrated that PERK regulates HF development and HF-induced lung inflammation [Liu et al. Hypertension. 2014; 64:738-44]. In collaborating with other groups, we have demonstrated that IRF1 [Jiang et al. Hypertension. 2014;64:77-86], IRF4 [Jiang DS et al. Hypertension, 2013;61:1193-202], IRF7 [Jiang et al. Hypertension. 2014, 63:713-22.], TRAF1 [Lu YY et al. Nature Communication. 2013;4:2852], and CXCR2 in regulating vascular macrophage accumulation and dysfunction in mice in response Ang-II and doca salt in mice [Wang et al. Circulation. 2016;134:1353-1368, PMCID: PMC5084654].

• Chen Y, Guo H, Xu D, Xu X, Wang H, Hu X, Lu Z, Xu Y, Kwak D, Gunther R, Huo Y, Weir EK. Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung Hypertension, 2012;59:1170-8. (corresponding author). PMCID: PMC3402091.
• Wang H, Hou L, Kwak D, Fassett J, Xu X, Chen A, Chen W, Blazar BR, Xu Y, Hall JL, Ge JB, Bache RJ, Chen Y. Increasing Regulatory T Cells With Interleukin-2 and Interleukin-2 Antibody Complexes Attenuates Lung Inflammation and Heart Failure Progression. Hypertension. 2016;68(1):114-22. (corresponding author). PMCID: PMC5022287
• Wang H, Kwak D, Fassett J, Hou L, Xu X, Burbach BJ, Thenappan T, Xu Y, Ge JB, Shimizu Y, Bache RJ,Chen Y. CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs. Hypertension. 2016 ;68(3):688-96. (corresponding author). PMCID: PMC5314944

• Yue W, Tong L, Liu X, Weng X, Chen X, Wang D, Dudley SC, Weir EK, Ding W, Lu Z, Xu Y, Chen Y. Short term 5 exposure caused a robust lung inflammation, vascular remodeling, and exacerbated transition from left ventricular failure to right ventricular hypertrophy. Redox Biol. 2019:101161. doi: 10.1016/j.redox.2019.101161. PMID: 30861460. (corresponding author).

• Wang H, Xu X, Fassett J, Kwak D, Liu X, Hu X, Falls TJ, Bell JC, Li H, Bitterman P, Bache RJ, Chen Y. Double stranded RNA–dependent Protein kinase deficiency protects the heart from systolic overload-induced congestive heart failure. Circulation, 2014;129:1397-406. (corresponding author). PMCID: PMC3972332

Our work has also contributed to identifying the roles of stress sensors (AMPKa2, K⁺ATP channels and adenosine kinase) in attenuating HF development. Metabolic stresses reduce cellular ATP content and
increase cellular AMPK and adenosine, which will activate stress sensors K⁺ATP channels, AMPK and adenosine kinase. We have demonstrated that stress sensors K⁺ATP channels [Hu X et al. Cir Res. 2008], AMPK [Zhang P. Hypertension 2008; Hu X. Hypertension 2011; Xu X. Hypertension 2014; Fassett AJP 2010, 2011] play an important role in limiting cardiac hypertrophy and HF. We also have demonstrated that adenosine kinase and adenosine receptors play important role in regulating HF development [Lu Z et al Circulation, 2008; Xu et al Hypertension 2008; Fassett J et al. AJP 2013; Xu et al. Hypertension 2014; Lu Z et al Circulation; 2008, Fassett et al 2011]. We demonstrated that stress sensor K⁺ATP channels and AMPKa2 play important roles in regulating mitochondrial biogenesis and HF development through modulating ERRα expression [Hu X et al Hypertension 2011; Hu et al Cir Res 2008]. We also demonstrated that PGC1α plays an important role in attenuating cardiac oxidative stress, mitochondria biogenesis, and HF development.

• Lu Z, John Fassett J, Xu X, Hu X, Zhu G, Jacobson MA, Robert J Bache RJ, Chen Y. Adenosine A3 receptor deficiency exerts unanticipated cardiac protective effects on the pressure overloaded induced ventricle hypertrophy. Circulation. 2008, 118:1713-21. (corresponding author), PMCID: PMC2803050.
• Hu X, Xu X, Lu Z, Zhang P, Fassett J, Zhang Y, Xin Y, Hall JL, Viollet B, Bache RJ, Huang Y, Chen Y*. AMP activated protein kinase-α2 regulates expression of estrogen-related receptor-α, a metabolic transcription factor related to heart failure development. Hypertension, 2011;58(4):696- 703. (Corresponding Author), PMCID: PMC3182261.
• Hu XL, Xu X, Flagg TP, Nichols CG, Bache RJ, Chen Y. Disruption of sarcolemmal ATP sensitive potassium channel activity represses PGC-1alpha expression and impairs the cardiac response to stress. Circulation Research. 2008, 103:1009-1017. Circulation Research. 2008 Oct, 103:1009- 1017. (corresponding author) PMID: 18802029, [PubMed - indexed for MEDLINE].
• Zhang P, Hu X, Xu X, Zhu G., Viollet B, Wayne Xu W, Wiczer B, Bernlohr DA, Bache RJ, Chen YJ. AMPKa2 deficiency exacerbates pressure-overload induced left ventricular hypertrophy, dysfunction and activation of mTOR pathway. Hypertension 2008, 52: 918-924. (corresponding author), PMCID:
• Lu Z, Xu X, Hu X, Fassett J, Zhu G, Tao Y, Li J, Zhang P, Zhao B, Chen Y*. PGC-1a regulates expression of myocardial mitochondrial antioxidants and myocardial oxidative stress after chronic systolic overload. Antioxid Redox Signal. 2010;13:1011-22. (Corresponding Author), PMCID: PMC2959178.

My works contribute to determine the roles of iNOS, PDE5 and SOD3 in ventricular hypertrophy, LV failure, and pulmonary hypertension. PDE5 selectively hydrolyzes cGMP, and selective inhibition of PDE5 can increase cGMP bioavailability. We provided evidence that PDE5 protein content is increased in cardiac myocytes in heart failure samples from human or mouse. We also provided the first direct evidence that oxidative stress regulates PDE5 expression in cardiac myocytes. Conversely, selective inhibition of PDE5 with sildenafil attenuated the TAC- induced LV oxidative stress and CHF [Lu et al Circulation, 2010]. We demonstrated that iNOS uncoupling contributes to systolic overload-induced heart failure, and selective iNOS inhibitor 1400W attenuated TAC-induced CHF and cardiac oxidative stress [Zhang et al Cir Res 2007]. We are the first demonstrating that inhibition of Nitric Oxide synthesis dramatically increased cardiac oxygen consumption in the failure heart [Chen et al. Circulation, 2002]. We further demonstrated that extracellular SOD (SOD3) plays an important role in attenuating TAC-induced CHF [Lu z et al Hypertension, 2008], and infarction-induced LV remodeling [van Deel et al. Free Radical Biology and Medicine, 2008]. We demonstrated that SOD3 plays an important role in attenuating the development of pulmonary artery hypertension [Xu D. et al Hypertension, 2011], and spontaneous renal failure and ventricular hypertrophy in rats [Guo H et al. Free Radical Biology & Medicine, 2020]. We also demonstrated that PGC-1a plays an important role in attenuating cardiac oxidative stress by increasing the expression of antioxidants [Lu et al. Antioxid Redox Signal 2010].

• Lu Z, Xu X, Hu X, Lee S, Traverse JH, Zhu G, Fassett J, Tao Y, Zhang P, Hall JL, dos Remedios C, Garry DJ, Chen Y. Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation. 2010;121:1474-83. (corresponding author) PMCID: PMC3110701
• Zhang P, Xu X, Hu X, van Deel ED, Zhu G, Chen Y. Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res. 2007;100:1089-98. (corresponding author), PMCID:
• Chen YJ, Traverse JH, Du R, Hou M, Bache RJ. Nitric oxide modulates myocardial oxygen consumption in the failing heart. Circulation 2002;106:273-9. PMID: 12105170. [PubMed - indexed for MEDLINE].
• Xu D, Guo H, Lu Z, Fassett J, Hu X, Xu Y, Tang Q, Hu D, Somani A, Geurts A, Ostertag E, Bache R, Weir EK, Chen Y. Exacerbated pulmonary arterial hypertension and right ventricular hypertrophy in animals with loss of function of extracellular superoxide dismutase. Hypertension, 2011, 2011 Aug;58(2):303-9. PMID: 21730301
• Guo H, Xu D, Kuroki M, Lu Z, Xu X, Geurts A, Osborn JW, Chen Y. Kidney failure, arterial hypertension and left ventricular hypertrophy in rats with loss of function mutation of SOD3. Free Radic Biol Med. 2020 Jan 21;. doi: 10.1016/j.freeradbiomed.2020.01.023. [Epub ahead of print] PubMed PMID: 31972339.

Defining Dimethylarginine dimethylaminohydrolase 1 (DDHA1) as the essential enzyme or sole enzyme in degrading endogenous NO inhibitor asymmetrical dimethylarginine (ADMA). Briefly, over 200 clinical studies/trials clearly indicate that accumulation of ADMA is one of the strongest independent risk factors for cardiovascular diseases, including hypertension, coronary disease, stroke, myocardial infarction and diabetes etc. For years, the scientific community has believed that there are two enzymes (DDAH1 and DDAH2) that degrade ADMA. It was believed that DDAH2 (but not DDAH1) plays the predominant role in maintaining vascular nitric oxide bioavailability through degrading ADMA. Using careful genetic over-expression or knockdown of DDAH1 and DDAH2 in vascular endothelial cells, we showed that DDAH1 is the critical enzyme for ADMA degradation, but our findings were repeatedly denied publication. Finally, by using our global DDAH1 KO mouse strain combined with other experimental approaches, we successfully demonstrated that DDAH1 is the essential enzyme for ADMA degradation, while DDAH2 plays no detectable role in ADMA degradation [Hu et al. Arterioscler Thromb Vasc Biol. 2011, 31:1540-6, PMC3117037]. In addition, by using our endothelial specific DDAH1 gene deficient, we demonstrated that DDAH1 localized in vascular endothelial cells plays an important role in regulating vascular NO bioavailability [Hu et al. Circulation, 2009, PMC2804399]. Our findings successfully challenged the longstanding dogma that DDHA2 was the predominant regulator of vascular NO bioavailability. Our findings are recognized as the major breakthrough in the ADMA field at the 5th and 7th International ADMA Conferences. We recently generated a DDAH1 KO rats, and it demonstrated that DDAH1 plays important role in pulmonary hypertension development [Wang D. 2019, PMID: 31402164]. Importantly, we were able to win over the scientists on different camps to work together to move the ADMA field forward.

• Hu XL, Xu X, Zhu G, Atzler D, Kimoto M; Chen J, Schwedhelm E, Lüneburg N, Böger RH, Zhang P, Chen Y. Endothelial specific DDAH1 gene deficient mice reveal that vascular endothelium is the primary site for removal of toxic methylarginines. Circulation, 2009;120:2222-9. (corresponding author). PMCID: PMC2804399
• Hu X, Atzler D, Xu X, Zhang P, Guo H, Lu Z, Fassett J, Schwedhelm E, Böger RH, Bache RJ, Chen Y. Global Dimethylarginine Dimethylaminohydrolase-1 (DDAH1) Gene-Deficient Mice Reveal That DDAH1 Is the Critical Enzyme for Degrading the Cardiovascular Risk Factor Asymmetrical Dimethylarginine. Arterioscler Thromb Vasc Biol. 2011, 31(7):1540-6. (corresponding author) PMCID: PMC3117037
• Zhang P, Hu X, Xu X, Chen Y, Bache RJ. Dimethylarginine dimethylaminohydrolase 1 modulates endothelial cell growth through nitric oxide and Arterioscler Thromb Vasc Biol. 2011 Apr;31(4):890- 7. PMID: 21212404, PMCID: PMC3064458
• Chen Y*, Li Y, Zhang P, Traverse JH, Hou M, Xu X, Kimoto M, Bache RJ. Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing Am J Physiol Heart Circ Physiol. 2005; 289:H2212-9. (The 1st author, and Corresponding Author). [PubMed - indexed for MEDLINE].
• Wang D, Li H, Weir EK, Xu Y, Xu D, Chen Y. Dimethylarginine dimethylaminohydrolase 1 deficiency aggravates monocrotaline-induced pulmonary oxidative stress, pulmonary arterial hypertension and right heart failure in rats. Int J Cardiol. 2019. S0167-5273(19)32132-1. doi: 10.1016/j.ijcard.2019.07.078. PMID: 31402164. (Corresponding author).

One of my contributions to the cardiovascular field is our finding in the field of translation initiation on HF development. It is generally believed that enhancing translation initiation will increase the cardiac protein synthesis to exacerbate cardiac hypertrophy and HF development. We have recently begun to focus on the role of mRNA translation initiation in development of HF. Surprisingly, we found that enhancing translation initiation by gene deletion of 4E binding proteins (4EBPs) or gene deletion of the eIF2α kinases PKR or GCN2 significantly protect the heart against TAC-induced heart failure without affect LV hypertrophy [Wang H et al. Circulation 2014; Lu Z et al. Hypertension 2014], indicating PKR, eIF4EBPs and GCN2 may be interesting therapeutic targets for treating CHF. Briefly, we studied the effect of gene deletion of the eIF2a kinases PKR and GCN2 on TAC-induced HF. Interestingly, we demonstrated that PKR expression is increased in heart failure myocardium while PKR KO exerts dramatic cardio-protective effects against TAC-induced HF [Wang H et al. Circulation 2014]. PKR KO also preserved SERCA2A expression, and reduced expression of apoptotic factors (caspase3 and Bax). Moreover, enhancing translation initiation by GCN2 KO attenuated TAC-induced HF [Lu Z et al. Hypertension 2014]. Interestingly, eIF2a kinase PERK KO exacerbated TAC-induced HF [Liu X et al. Hypertension 2014]. The different phenotypes observed in PKR KO, GCN2 KO and PERK KO indicate that these eIF2a kinases exert stress-specific effect(s) on HF development. We recently further identified that enhancing translation initiation by 4EBPs deletion profoundly attenuated pressure overload induced HF that was associated with a dramatic increase of myocardial SERCA2a protein content without affect its mRNA level (SERCA2a is one of the most important therapeutic targets for treating HF). A manuscript describing this major finding is now submitted to Circulation in an invited 4th revision.

• Wang H, Xu X, Fassett J, Kwak D, Liu X, Hu X, Falls TJ, Bell JC, Li H, Bitterman P, Bache RJ, Chen Y. Double stranded RNA–dependent Protein kinase deficiency protects the heart from systolic overload-induced congestive heart Circulation, 2014;129:1397-406. (corresponding author). PMCID: PMC3972332.
• Lu Z, Hu X, Fassett J, Kwak D, Wang H, Liu X, Hu X, Guo H, Xu D, Yan S, McFalls E, Lu F, Bache RJ, Chen Y. Loss of the eIF2a kinase GCN2 protects mice from pressure overload induced congestive heart failure without affecting ventricular hypertrophy. Hypertension, 2014; 63:128-35. (corresponding author). PMCID: in
• Liu X, Lu Z, Xu X, Kwak D, Fassett F, Wang H, Hu X, Yan S, Xu D, Wei Y, Cavener D, Bache RJ, Chen Y. Endoplasmic Reticulum Stress Sensor Protein Kinase R–LikeEndoplasmic Reticulum Kinase Protects Against Pressure Overload–Induced Heart Failure and Lung Remodeling. Hypertension. 2014; 64:738-44. (corresponding author). PMCID: PMC4162806

Complete List of Published Work in MyBibliography: https://www.ncbi.nlm.nih.gov/sites/myncbi/yingjie.chen.1/bibliography/40696749/public/?sortby=pubDate&sdire ction=descending

Complete List of Published Work in Google Scholar:https://scholar.google.com/citations?user=NMLVZc0AAAAJ&hl=en

Research Support

Ongoing Research Support

NIH/NHLBI R01HL161085-01 (Chen), 1/1/2022-8/31/2025
Title: Mechanism of PD1 on cardiac inflammation resolution during heart failure development
Role: Principal Investigator

5R01HL139797-04 (Yingjie Chen), 9/1/2018-6/30/2022 (no cost extension to 6/30/2023)
Title: Mechanisms of Treg and IL-35 in Regulating LV Failure-induced Lung Remodeling and Right Heart Hypertrophy
Role: Principal Investigator

1R01HL148191 (SHAHUL, SAJID), 9/1/2021-6/30/2026
Title: Aspirin to prevent cardiac dysfunction in preeclampsia Role: Co-Investigator (5% effort)