Proteomic Approach to the Study of Cardiovascular Disease

My research seeks a better understanding of molecular mechanisms involved in cardiovascular diseases (hypotrophy, heart failure and ischemia), hibernation and aging using proteomic approaches.

(1) Clinically, the decompensated stage of HF is usually preceded by chronic, compensatory cardiac hypertrophy (LVH). The mechanisms that precipitate the transition from hypertrophy to failure remain largely unknown. We hypothesize that this transition involves both quantitative and qualitative changes in protein turnover. We utilized a novel canine model, where HF is induced in the setting of stable, severe, chronic (2 yrs) LVH to examine proteome alterations between LVH and HF. We anticipate these proteomic studies will provide insights into the pathogenesis of HF.

(2) Mammalian hibernation is a unique strategy for winter survival in response to limited food availability and harsh climate. Under these deleterious and stressful conditions, the heart of non-hibernating animals would develop serious ventricular arrhythmias or cease contraction. However, the heart of hibernating animals exhibits remarkable tolerance and resistance to the impact of these stresses. We observed that hibernating mammals such as woodchucks ( Marmota monax ) demonstrate a changed phenotype from summer to winter. They exhibit powerful myocardial protection in the winter against ischemia/reperfusion injury compared to woodchucks in summer. In fact, hibernating animals are “prepared” for winter by evoking their intrinsic cardioprotective mechanisms. We investigate the cellular and molecular mechanisms involved in natural resistance to cardiac stresses in hibernating mammals and to uncover the master “switch” from non-hibernation to hibernation. Understanding the cardiac adaptive mechanisms in hibernators may suggest new strategies to protect myocardium of non-hibernating animals, especially humans, from cardiac dysfunction induced by hypothermic stresses and myocardial ischemia.

(3) Another research interest involves the use of proteomics to characterize proteins involved in aging and gender differences. We previously demonstrated that genetic deletion of type 5 adenylyl cyclase (AC5) in mice leads to extended lifespan and increased stress resistance. Using a proteomic approach, we demonstrated that the Raf/MEK/ERK pathway plays an essential role in mediating longevity and stress resistance in AC5 knockout mice. In addition to the AC5 knockout mouse, additional aging studies are being conducted in a primate model.

(4) Our lab also supports proteomic research for other investigators in the department.

Representive Publications:

1.  Yan L, Vatner DE, O'Connor JP, Ivessa A, Ge H, Chen W, Hirotani S, Ishikawa Y, Sadoshima J, and Vatner SF. Type 5 adenylyl cyclase disruption increases longevity and protects against stress Cell, 2007, 130: 247-258.

2.  Peter PR, Brady JE, Yan L , Chen W, Yang G, Engelhardt S, Wang Y, Sadoshima J, Vatner SF, and Vatner DE.  Inhibition of p38 a MAPK rescues overexpressed beta-2 -adrenergic receptor but not beta-1 - adrenergic receptor induced cardiomyopathy J. Clin Invest, 2007, 117: 1335-1343.

3.  Kudej RK, Shen Y-T, Peppas AP, Huang C-H, Chen W, Yan L , Dorothy E. Vatner, Stephen F. Vatner, Obligatory role of cardiac nerves and 1 -adrenergic receptors for the second window of ischemic preconditioning in conscious pigs Circ Res, 2006, 99: 1270-6.

4.  Depre C, Wang Q, Yan L , Hedhli N, Peter P, Chen L, Hong C, Hittinger L, Ghaleh B, Sadoshima J, Vatner DE , Vatner SF, Madura K. Activation of the cardiac proteasome during pressure overload promotes ventricular hypertrophy. Circulation, 2006, 114: 1821-8.

5.  Yatani A, Shen Y-T, Yan L , Chen W, Kim S-J, Sano K, Irie K, Vatner SF and Vatner DE.  Down regulation of the L-type Ca2+ channel, GRK2, and phosphorylated phospholamban: protective mechanisms for the denervated failing heart . J Mol Cell Cardiol., 2006, 40: 619-28.

6.  Yan L , Sadoshima J, Vatner DE , Vatner SF.  Autophagy: a novel protective mechanism in chronic ischemia.   Cell Cycle, 2006, 5: 1175-1177.

7.  Yan L , Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, Yang G, Matsui Y, Sadoshima J, Vatner SF.  Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci. , 2005, 102: 13807-12.

8.  Yan L, Ge H, Li, Lieber S, Natividad, F, Resuello, Ranillo RG, Kim S-J, Akeju, S, Sun, A, Loo K, Peppas T, Franco R, Lewandowski, E. Douglas, Thomas AP, Vatner, SF, Vatner DE.  Gender-specific proteomic alterations in glycolytic and mitochondrial pathways in aging monkey hearts, J Mol Cell Cardiol., 2004, 37: 921-929.