Intracoronary Adenovirus-Mediated Delivery and Overexpression of the β2-Adrenergic Receptor in the Heart


Background—Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β2-adrenergic receptors (β2ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human β2AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. Methods and Results—Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-βGal) or the β2AR (Adeno-β2AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex– and right coronary artery–mediated delivery of Adeno-β2AR resulted in ≈10-fold overexpression in a chamber-specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β2ARs in the LV improved global LV contractility, as measured by dP/dtmax, at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. Conclusions—Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the β2AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.





Shah, A. S., R. E. Lilly, et al. (2000). "Intracoronary Adenovirus-Mediated Delivery and Overexpression of the β2-Adrenergic Receptor in the Heart." Circulation 101(4): 408-414.

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Shah, AS, RE Lilly, AP Kypson, O Tai, JA Hata, A Pippen, SC Silvestry, RJ Lefkowitz, et al. (2000). Intracoronary Adenovirus-Mediated Delivery and Overexpression of the β2-Adrenergic Receptor in the Heart. 10.1161/01.CIR.101.4.408 Retrieved from

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Robert J. Lefkowitz

The Chancellor's Distinguished Professor of Medicine

Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win.

Robert J. Lefkowitz, M.D. is Chancellor’s Distinguished Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the Howard Hughes Medical Institute since 1976. Dr. Lefkowitz began his research career in the late 1960’s and early 1970’s when there was not a clear consensus that specific receptors for drugs and hormones even existed. His group spent 15 difficult years developing techniques for labeling the receptors with radioactive drugs and then purifying the four different receptors that were known and thought to exist for adrenaline, so called adrenergic receptors. In 1986 Dr. Lefkowitz transformed the understanding of what had by then become known as G protein coupled receptors because of the way the receptor signal for the inside of a cell through G proteins, when he and his colleagues cloned the gene for the beta2-adrenergic receptor. They immediately recognized the similarity to a molecule called rhodopsin which is essentially a light receptor in the retina. This unexpected finding established the beta receptor and rhodopsin as the first member of a new family of proteins. Because each has a peptide structure, which weaves across the cell membrane seven times, these receptors are referred to as seven transmembrane receptors. This super family is now known to be the largest, most diverse and most therapeutically accessible of all the different kinds of cellular receptors. There are almost a thousand members of this receptor family and they regulate virtually all known physiological processes in humans. They include the receptors not only to numerous hormones and neurotransmitters but for the receptors which mediate the senses of sweet and bitter taste and smell amongst many others. Dr. Lefkowitz also discovered the mechanism by which receptor signaling is turned off, a process known as desensitization. Dr. Lefkowitz work was performed at the most fundamental and basic end of the research spectrum and has had remarkable consequences for clinical medicine. Today, more than half of all prescription drug sales are of drugs that target either directly or indirectly the receptors discovered by Dr. Lefkowitz and his trainees. These include amongst many others beta blockers, angiotensin receptor blockers or ARBs and antihistamines. Over the past decade he has discovered novel mechanisms by which the receptors function which may lead to the development of an entirely new class of drugs called “biased agonists”. Several such compounds are already in advanced stages of clinical testing. Dr. Lefkowitz has received numerous honors and awards, including the National Medal of Science, the Shaw Prize, the Albany Prize, and the 2012 Nobel Prize in Chemistry. He was elected to the USA National Academy of Sciences in 1988, the Institute of Medicine in 1994, and the American Academy of Arts and Sciences in 1988.


Donald D. Glower

Professor of Surgery

Current clinical research projects examine the effects of patient characteristics and surgical technique in outcome after minimally invasive cardiac surgery, valve repair and replacement, and coronary artery bypass grafting.
Prior work has examined the role of surgical therapy versus medical therapy in aortic dissection, load-independent means to quantify left and right ventricular function, and management of complex coronary disease.

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