Kerry Strong Russell, MD, PhD Associate Professor of Medicine Cardiovascular Medicine

B.A. Rice University, 1985; MD, PhD, University of Texas - Houston and MD Anderson Cancer Center, 1992; Residency Training in Internal Medicine - Yale New Haven Hospital, 1995; Cardiology Fellowship Training - Yale School of Medicine, 2000; Joined Yale Faculty, 2000.

Signaling pathways in vascular function and heart failure

Our research broadly encompasses 2 common themes in cardiovascular medicine: preservation of cardiac function and promotion of angiogenesis. We have chosen to focus on 2 major targets in the cardiovascular system that could potentially be manipulated to achieve the goals of myocyte preservation and angiogenesis. 1) The first of these targets is the neuregulin/erbB ligand/receptor system. Evidence for the importance of this signaling system in the heart comes from clinical data showing that interruption of this system (e.g. using Herceptin in breast cancer patients) leads to depression of cardiac function, ultimately leading to heart failure in some patients. Our work over the past few years has shown that activation of this signaling system can protect cardiac myocytes against injury in response to ischemia and can promote angiogenesis. 2) The second target under investigation is the IL-6/STAT3 signaling cascade. Clinical data has revealed a paradoxical relationship between detrimental and protective effects of several "pro-inflammatory" cytokine pathways, including that of IL-6, in patients with heart failure. Our data suggests that one particular downstream target of IL-6 signaling, the STAT3 protein, may be important for the cardioprotective effects of IL-6. We hope that unraveling the details of this signaling pathway will provide novel targets to protect the heart in the setting of ischemic or inflammatory injury. Additional areas of interest include gender differences in cardiovascular disease risk (including role of estrogen in vascular and cardiomyocyte protection), and use of non-invasive imaging (especially echocardiography) for evaluation of cardiac function in small animal models.

Russell KS, Hung MC. Transcriptional repression of the neu protooncogene by estrogen stimulated estrogen receptor. Cancer Res. 1992;52:6624-6629.

Russell KS, Lee EK, Kiyokawa N, Hideyuki S, Hung MC. Effects of estrogen receptor expression of growth and transformation of cells overexpressing neu. Oncology Reports. 1996;3:433-437.

Cuff CA, Schwartz J, Bergman CM, Russell KS, Bender JR, Ruddle NH. Lymphotoxin alpha3 induces chemokines and adhesion molecules: insight into the role of LT alpha in inflammation and lymphoid organ development. J Immunol. 1998;161(12):6853-6860.

Russell KS, Stern DF, Polverini PJ, Bender JR. Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. Am J Physiol. 1999;277(6 Pt 2):H2205-2211.

Haynes MP, Russell KS, Bender JR. Molecular mechanisms of estrogen actions on the vasculature. J Nucl Cardiol. 2000;7(5):500-508.

Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, Sessa WC, Bender JR. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res. 2000;87(8):677-682.

Russell KS, Haynes MP, Caulin-Glaser T, Rosneck J, Sessa WC, Bender JR. Estrogen stimulates heat shock protein 90 binding to endothelial nitric oxide synthase in human vascular endothelial cells. Effects on calcium sensitivity and NO release. J Biol Chem. 2000;275(7):5026-5030.

Russell KS, Haynes MP, Sinha D, Clerisme E, Bender JR. Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. Proc Natl Acad Sci U S A. 2000;97(11):5930-5935.

Haynes MP, Li L, Russell KS, Bender JR. Rapid vascular cell responses to estrogen and membrane receptors. Vascul Pharmacol. 2002;38(2):99-108.

Haynes MP, Li L, Sinha D, Russell KS, Hisamoto K, Baron R, Collinge M, Sessa WC, Bender JR. Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J Biol Chem. 2003;278(4):2118-2123.

Jacoby JJ, Kalinowski A, Liu MG, Zhang SS, Gao Q, Chai GX, Ji L, Iwamoto Y, Li E, Schneider M, Russell KS, Fu XY. Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci U S A. 2003;100(22):12929-12934.

Park SY, Cho YR, Finck BN, Kim HJ, Higashimori T, Hong EG, Lee MK, Danton C, Deshmukh S, Cline GW, Wu JJ, Bennett AM, Rothermel B, Kalinowski A, Russell KS, Kim YB, Kelly DP, Kim JK. Cardiac-specific overexpression of peroxisome proliferator-activated receptor-{alpha} causes insulin resistance in heart and liver. Diabetes. 2005;54(9):2514-2524.

Park SY, Cho YR, Kim HJ, Higashimori T, Danton C, Lee MK, Dey A, Rothermel B, Kim YB, Kalinowski A, Russell KS, Kim JK. Unraveling the temporal pattern of diet-induced insulin resistance in individual organs and cardiac dysfunction in C57BL/6 mice. Diabetes. 2005;54(12):3530-3540.

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Last modified:Wednesday, 09-Apr-2008 12:23:44 EDT (PL).