People
- Department of Physiology
- About Physiology and Biophysics
-
Education
- Physiology and Biophysics Educational Programs Home
- Graduate Program
- Undergraduate Research Experience
- Seminar and Lecture Series
- Seminar Series Archives
-
Research
- Physiology and Biophysics Research Home
- Core Facilities
- Programs
- Graduate Program Research
- Publications
- Research Links
- Resources
Chen Research Summary
I have had a longstanding interest in understanding the molecular mechanisms of Heart Failure (HF) development, HF progression (the transition from left heart failure to type-2 pulmonary hypertension and right heart failure), and vascular endothelial dysfunction in HF. My overall goal is to understand the poor prognosis of HF and identify new targets and methods for treating or halting HF progression. My major contributions to science include the following subjects:
Identification of the important role of lung inflammation in HF progression. We were the first to demonstrate that end-stage HF causes massive lung inflammation. It is well known that end-stage HF causes a dramatic increase of lung weight, a condition often described as lung edema. We provided the first direct experimental 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 dense 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. Following the observation that inhibition of the lung damage/inflammation can stop or partially reverse the progression of end-stage HF, we have made significant efforts to identify the factors responsible for HF-related tissue inflammation. We have demonstrated that induction of T regulatory cells is sufficient to attenuate HF progression and development [Wang et al 2016, PMC5022287]. We further showed that inhibition of T cell activation by CD28 KO, B7 KO or depletion D11c-positive antigen-presenting cells significantly attenuates TAC-induced cardiac and lung inflammation and HF development [Wang et al 2016b, Wang et al. 2017, PMID: 28349258]. Recently, we demonstrated that the increase of lung inflammation induced by short term PM2.5 exposure profoundly exacerbates lung vessel remodeling and fibrosis, as well as RV hypertrophy, while LV hypertrophy and function are unaffected in mice with existing LV failure [Yue et al. 2019, PMID: 30861460]. These findings demonstrate that lung inflammation can exacerbate lung and RV remodeling without directly affecting LV function.
In addition, we have shown 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 of its expression in leukocytes [Wang et al 2014, PMC3972332]. We also reported that PERK regulates HF development and HF-induced lung inflammation [Liu et al. Hypertension. 2014; 64:738-44]. In collaboration with other groups, we have published data showing 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 regulate vascular macrophage accumulation and dysfunction in mice in response to Ang-II and doca salt [Wang et al. Circulation. 2016;134:1353-1368, PMCID: PMC5084654].
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) played the predominant role in maintaining vascular nitric oxide bioavailability through the degradation of 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 model, 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 were recognized as the major breakthrough in the ADMA field at the 5th and 7th International ADMA Conferences. We recently generated a DDAH1 KO rat model, and used it to demonstrate that DDAH1 plays an important role in the development of pulmonary hypertension [Wang D. 2019, PMID: 31402164]. Importantly, we were able to win over scientists in different camps to work together to move the ADMA field forward.
Our work has also contributed to the identification of 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 AMP and adenosine, which will activate the 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 shown 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 reported 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, mitochondrial biogenesis, and HF development.
My work has helped 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 humans and from mice. 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 were the first to demonstrate that inhibition of Nitric Oxide synthesis dramatically increases cardiac oxygen consumption in the failing heart [Chen et al. Circulation, 2002]. We further showed 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 showed that SOD3 plays an important role in attenuating the development of pulmonary arterial 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 have also shown 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].
One of my contributions to the cardiovascular field is our finding in the area 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 the development of HF. Surprisingly, we found that enhancing translation initiation by gene deletion of 4E binding proteins (4EBPs) or gene deletion of the eIF2 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 that 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 found 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 affecting 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.