August 2012 Researcher of the Month - Lingjie Wang, MD, PhD

Current Research:
Diabetes Mellitus (DM) is highly prevalent in the adult population worldwide. Obesity and insulin resistance have been associated with type II DM. Recent studies have indicated that high fat diet (HFD) potentiates interaction between oxidized lipids and proteins leading to the generation of Advanced Glycation Endproducts (AGEs) and pre-AGEs.  Studies have also shown that HFD up regulates the Receptor for Advanced Glycation Endproducts (RAGE).  AGE-RAGE interaction up regulates cytokines, adhesion molecules, and activates Nuclear Factor-kB.

The goal of my research is to investigate if the hearts in RAGE null mice are protected from mitochondrial dysfunction when fed a high fat diet, and to further illustrate the potential molecular mechanism-involved cardiac metabolism in RAGE and HFD induced obesity.

Publications:
1. Liu YH, Su JY, Wang LJ, Li JP, Zhou QF, Gan Q, Chai XC, Dai LY, Zhang FR, Shen WF. Impact of potentially lethal ventricular arrhythmias on long-term outcome in patients with chronic heart failure. Chin Med J (Engl). 2012 Feb;125(4):563-8.

2. Lu L, Peng WH, Wang W, Wang LJ, Chen QJ, Shen WF. Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats.  J Zhejiang Univ Sci B. 2011 Aug;12(8):652-9.

3. Cao J, Zhu T, Lu L, Geng L, Wang L, Zhang Q, Yang K, Wang H, Shen W. Estrogen induces cardioprotection in male C57BL/6J mice after acute myocardial infarction via decreased activity of matrix metalloproteinase-9 and increased Akt-Bcl-2 anti-apoptotic signaling. Int J Mol Med. 2011 Aug;28(2):231-7.

4.  Li JP, Lu L, Wang LJ, Zhang FR, Shen WF. Increased serum levels of S100B are related to the severity of cardiac dysfunction, renal insufficiency and major cardiac events in patients with chronic heart failure. Clin Biochem. 2011 Aug;44(12):984-8.

5. Wang W, Peng WH, Lu L, Zhang RY, Zhang Q, Wang LJ, Chen QJ, Shen WF. Polymorphism on chromosome 9p21.3 contributes to early-onset and severity of coronary artery disease in non-diabetic and type 2 diabetic patients. Chin Med J (Engl). 2011 Jan;124(1):66-71.  

6. Yan X, Sano M, Lu L, Wang W, Zhang Q, Zhang R, Wang L, Chen Q, Fukuda K, Shen W. Plasma concentrations of osteopontin, but not thrombin-cleaved osteopontin, are associated with the presence and severity of nephropathy and coronary artery disease in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2010 Oct 29;9:70.

7. Wang LJ, Lu L, Zhang FR, Chen QJ, De Caterina R, Shen WF.Increased serum high-mobility group box-1 and cleaved receptor for advanced glycation endproducts levels and decreased endogenous secretory receptor for advanced glycation endproducts levels in diabetic and non-diabetic patients with heart failure. Eur J Heart Fail. 2011 Apr;13(4):440-9.

8. Chen QJ, Lu L, Jin C, Wang LJ, Zhang RY, Zhang Q, Hu J, Yang ZK, Shen WF.Insertion/insertion genotype of α(2B)-adrenergic receptor gene polymorphism is associated with silent myocardial ischemia in patients with type 2 diabetes mellitus. Clin Biochem. 2010 Oct;43(15):1201-4.

9. Shi C, Wang LJ, Hu DF, Li JP, Zhu TQ, Shan Y, Zhao JR, Zhang FR, Shen WF. Prevalence, clinical characteristics and outcome in patients with chronic heart failure and diabetes.  Chin Med J (Engl). 2010 Mar 20;123(6):646-50. 

10. Lu L, Zhang Q, Xu Y, Zhu ZB, Geng L, Wang LJ, Jin C, Chen QJ, Schmidt AM, Shen WF. Intra-coronary administration of soluble receptor for advanced glycation end-products attenuates cardiac remodeling with decreased myocardial transforming growth factor-beta1 expression and fibrosis in minipigs with ischemia-reperfusion injury. Chin Med J (Engl). 2010 Mar 5;123(5):594-8. 

11. Wang L, Lu L, Zhang F, Chen Q, Shen W.  Polymorphisms of beta-adrenoceptor and natriuretic peptide receptor genes influence the susceptibility to and the severity of idiopathic dilated cardiomyopathy in a Chinese cohort. J Card Fail. 2010 Jan;16(1):36-44.

12. Lu L, Pu LJ, Zhang Q, Wang LJ, Kang S, Zhang RY, Chen QJ, Wang JG, De Caterina R, Shen WF Increased glycated albumin and decreased esRAGE levels are related to angiographic severity and extent of coronary artery disease in patients with type 2 diabetes.  Atherosclerosis. 2009 Oct;206(2):540-5.

13. Yan XX, Lu L, Peng WH, Wang LJ, Zhang Q, Zhang RY, Chen QJ, Shen WF.  Increased serum HMGB1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients.  Atherosclerosis. 2009 Aug;205(2):544-8.

14. Ruan W, Lu L, Zhang Q, Cao M, Zhu ZB, Wang LJ, Shen WF.Serial assessment of left ventricular remodeling and function by echo-tissue Doppler imaging after myocardial infarction in streptozotocin-induced diabetic swine.  J Am Soc Echocardiogr. 2009 May;22(5):530-6. 

Abstracts and meetings attended:
1. Wang LJ,  Song F, Ananthakrishnan R, Lu L, Shen WF, Schmidt AM, Ramasamy R. RAGE Deletion promotes mitochondrial biogenesis in high fat diet fed mice. Cardiac Metabolism in Hypertrophy and Failure. 10th Annual Meeting of the Society for Heart and Vascular Metabolism. Oxford, UK., 2012. (Poster)

2. Wang LJ, Lu L, Zhang FR, Chen QJ, Shen WF. Increased serum HMGB1 and cRAGE levels, and decreased esRAGE levels in diabetic or non-diabetic patients with chronic heart failure. 1st World Congress of Cardiology (World Heart Federation). Beijing, China. 2010. (Oral Presentation).

3. Wang LJ, Lu L, Zhang FR, Chen QJ, Shen WF. Increased serum Apelin levels with diabetic cardiomyopathy.12th National Cardiovascular Disease Academic Council. Dalian, China.2009 (Oral Presentation).

Future Plans:
Cardiovascular diseases, including heart failure, are still the primary cause of high mortality and morbidity associated with diabetes mellitus. To understand the mechanism of diabetes mellitus participating in the development and progression of heart failure, such as dysfunction of the post-modification process of protein (acetylation and glycation, et al.) involving in the cardiac metabolism, may give us an important insight into the treatment of heart failure in clinical practice.

It is challengeable but meaningful to translate the bench experiment results into bedside practice. As a physician of cardiology, I feel lucky that I own valuable training experience in both basic research and clinical practice involving diabetes mellitus and cardiovascular diseases.

My future studies will continue focusing on the mechanism of diabetes-accelerated heart failure.  I will examine the mitochondrial dysfunction induced by diabetes (and/or obesity) that impacts cardiac metabolism. I am confident that my ongoing scientific research will ultimately be beneficial to the individual and systemic treatment of my patients with cardiovascular diseases in the future.