The focus of our lab is in understanding the cardiovascular consequences of obesity. Obesity is arguably the greatest health threat in Western medicine, afflicting over 1/3 of the U.S. population and growing yet more prevalent. While enormous progress has been achieved in recognizing the prevalence of end-stage diseases like obesity and hypertension in obesity, the unexplored frontier lies in identifying therapeutic opportunities for intervention prior to the development of these conditions. It is this frontier that our lab is dedicated to explore. Specific areas of interest include:

Determining the effects of pre-diabetic metabolic disease on vascular function: While insulin resistance is well-recognized as a precursor state to diabetes, emerging evidence indicates that it is also a risk factor for cardiovascular disease. Using dietary models of sugar loading, evidence has mounting of impaired control of endothelial function and altered regulation of blood pressure in insulin resistance. What remains unclear is the extent to which the vascular dysfunction in obesity can be attributed to the metabolic changes associated with obesity. To address this issue, we have generated dual transgene mice on a eptin-deficient background. The second transgene is Protein Tyrosine Phosphotase 1-B, a key regulatory enzyme that causes insulin resistance. By deleting this enzyme, a strain of mice is generated that is still obese (Mouse #250) compared to control (Mouse #24) but insulin sensitive with a normal metabolic profile. The next phase of these studied will determine if cardiovascular dysfunction observed in normal obese mice (#248) are corrected in the dual transgene.

Endocrine dysfunction as a cause of cardiovascular disease in obesity: While metabolic function is well-known to accompany increases in adiposity, it is also known that other, parallel endocrinopathy occurs. Our lab is interested in two specific kinds of endocrine disease: hypothyroidism and hyperadrenalism. Both conditions are evident on obese individuals but the cardiovascular consequences are unknown. The specific interest in our lab is the extent to which these two condition impact on signaling in the adrenergic receptor pathways present in vascular smooth muscle. Alpha adrenergic tone is upregulated in the skeletal muscle circulation and alpha adrenergic receptors are at least in part regulating by glucorticoids, the hormones that are increased in hyperadrenal states. In contrast, beta adrenergic vasodilation is reduced in obesity and beta adrenergic receptor expression is determined by thyroid status, which is reduced in obesity. Thus, the shift to a more constricted state may be driven by an imbalance in these two hormone system. The goal of this project is to determine the extent to which normalization of hormone status improves cardiovascular function in obesity.

Regulation of cardiovascular during stress: Another cardiovascular deficit in obese individuals is the inability to properly regulate blood pressure during periods of psychological stress. Obesity appears to impair the proper integration of neural and vascular signal during periods of psychological stress and thus normal events can precipitate cardiovascular exigencies in obese individuals. In this project, we are attempting to determine the extent to which neural control of the circulation is altered at the vascular level and whether this dysfunction contributes to impairment in both the acute and chronic regulation of blood pressure.


Adrenal Gland from an Obese rat

Grant Support as Principal Investigator

NIH R01 HL 76533 - " Mechanisms of Peripheral Microvascular Disease"
Active: 2005-2009 - $1,358,000 total costs
PI - 30%

Honors and Awards

Awards

• Microcirculation Society Young Investigator Travel Award 2001

Honors

• Featured research: National report of the AHA Wisconsin Affiliate 1999

Invited Speaker

• Lankenau Research Institue, Philadelphia, PA - October 2001
• Medical College of Georgia, Augusta GA - November 2001
• University of South Carolina -Aiken -March 2002
• University of Cincinnati - Cincinnati - January 2003
• University of Mississippi Medical Center - Jackson, MS - August 2003
• Louisiana Health Sciences Center - New Orleans, LA - August 2003
• American Heart Association National Meeting - New Orleans - November 2004 (abbreviated form)
• University of Georgia - Athens, GA - February 2006

• Southeastern Lipid Research Club, Georgia - September 2003
• Medical College of Georgia, Pharmacology - January 2004

• Texas A&M University - September 2005
• Virginia Commonwealth University - September 2005
• American Heart Association National Meeting - Dallas - November 2005 (abbreviated form)
• Experimental Biology - San Francisco, April 2006 (abbreviated form)
• European Council on the Microcirculation - Amsterdam, August 2006
• Case Western Reserve University - Cleveland, OH - November 2006

Publications

Frisbee, J.C. and D. W. Stepp. Impaired NO-dependent dilation in the skeletal microvasculature of the Obese Zucker Rat. Am. J. Physiol. 281(3):H1304-11, 2001.

Stepp, D.W. and J.C. Frisbee. Augmented adrenergic vasoconstriction in hypertensive diabetic Obese Zucker Rats Am. J. Physiol. 282: H816-H820, 2002

Stepp, D.W., D.M. Pollock and J. C. Frisbee. Low-Flow Vascular Remodeling in the Metabolic Syndrome X. Am J Physiol Heart Circ Physiol. 286(3):H964-70, 2004

Fulton, D.J., M.B. Harris, R. C. Venema and D. W. Stepp. Insulin Resistance Does Not Diminish eNOS Expression, Phosphorylation or Binding to HSP90. Am J Physiol Heart Circ Physiol. 287(6):H2384-93, 2004.

Schreihofer, A. M., C. D. Hair and D. W. Stepp. Altered blood volume and vascular reactivity in lean vs. obese Zucker rats Am J Physiol Reg ;288(1):R253-61, 2005.

Romanko, O.P. and D. W. Stepp. Reduced constrictor reactivity balances reduced dilator reactivity in the mesenteric circulation of Obese Zucker rats. Am J Physiol Heart Circ Physiol. 289(5):H2097-102, 2005.

D'Angelo, G.D., A. El-Markaby, D. M. Pollock, and D. W. Stepp. Fructose-Feeding Increases Insulin Resistance But Not Blood Pressure In Sprague-Dawley Rats. Hypertension Oct;46(4):806-11., 2005

Stepp, D.W. The effects of obesity on perfusion: nitric oxide and beyond Clin. Exp. Phys. Pharm May-Jun;33(5-6):407-14., 2006

Prakash, R. J. D. Mintz and D.W.Stepp. Obesity does not diminish coronary microvascular function in the Obese Zucker Rat Microcirculation (In press)

D'Angelo, G.D., J.D. Mintz, D. M. Pollock, and D. W. Stepp. Pressor response to acute environmental stress is augmented in the obese Zucker rat. Hypertension (In press)

Education and Training

Research Experience & Academic Appointments

2001-Present

Institutional Faculty List