A persistent question in cardiovascular gene transfer concerns whether an exogenously delivered gene can increase function of the failing heart. Here we test the hypothesis that intracoronary delivery of adenovirus encoding adenylylcyclase type VI (Ad.ACVI) in the setting of active heart failure will increase function of the failing heart. As a model of heart failure, we used transgenic mice with dilated and poorly functioning hearts resulting from cardiac-directed expression of Galphaq.Galphaq mice with equivalent pretreatment impairment in left ventricular (LV) function (echocardiography) received 2.5x1010 viral particles of Ad.ACVI or Ad.EGFP (enhanced green fluorescent protein), or saline, by indirect intracoronary delivery. Serial echocardiograms obtained before and 14 days after gene transfer showed that Ad.ACVI increased LV ejection fraction (p<0.01) and velocity of circumferential fiber shortening (p<0.03). Detailed measurements in isolated hearts showed that ACVI gene transfer increased LV positive dP/dt (p=0.02) and LV negative dP/dt (p=0.01). Gene transfer was confirmed by polymerase chain reaction. These data show that, in an animal model that mimics key aspects of clinical congestive heart failure, cardiac gene transfer of ACVI increases function of the failing heart.
"When this protein was overexpressed in mice with cardiomyopathy-induced by overexpression of Ga-q enhancement of cyclase increased survival, possibly by a mechanism that involves enhanced response to catecholamines (Roth et al. 1999, Rebolledo et al. 2006). However, transgenic expression of the same gene did not cause significant effects on heart rate or basal function (Roth et al. 2003), although it did improve survival in a coronary artery ligation model (Takahashi et al. 2006). "
[Show abstract][Hide abstract] ABSTRACT: Protein kinase A (PKA) is an evolutionarily conserved protein which has been studied in model organisms from yeast to man. Although the cAMP-PKA signaling system was the first mammalian second messenger system to be characterized, many aspects of this pathway are still not well understood. Owing to findings over the past decade implicating PKA signaling in endocrine (and other) tumorigenesis, there has been renewed interest in understanding the role of this pathway in physiology, particularly as it pertains to the endocrine system. Because of the availability of genetic tools, mouse modeling has become the pre-eminent system for studying the physiological role of specific genes and gene families as a means to understanding their relationship to human diseases. In this review, we will summarize the current data regarding mouse models that have targeted the PKA signaling system. These data have led to a better understanding of both the complexity and the subtlety of PKA signaling, and point the way for future studies, which may help to modulate this pathway for therapeutic effect.
Endocrine Related Cancer 06/2009; 16(3):773-93. DOI:10.1677/ERC-09-0068 · 4.81 Impact Factor
"Exogenous gene transfer will be required if AC6 is ever to be applied in the treatment of clinical heart failure. Mice with Gaq cardiomyopathy received indirect intracoronary delivery of an adenovirus vector encoding AC6, and LV systolic and diastolic function were increased fourteen days after delivery (Rebolledo et al., 2006). However, this study used thoracotomy and aortic and pulmonary artery cross clamping to deliver the adenovirus vector, a technique that will not be applicable to patients with severe CHF. "
[Show abstract][Hide abstract] ABSTRACT: Congestive heart failure (CHF) affects more than five million people in the United States and results in considerable morbidity, mortality, and economic costs. Patients with class III and IV CHF have a 40% to 50% probability of dying 5 years after symptom onset despite optimal therapy, a prognosis worse than many cancers. A variety of drugs and devices have improved survival-the 50% survival time in 1980 was just 18 months-but the outlook for patients remains dismal and the prevalence of CHF continues to increase. This unmet medical need underscores the importance of developing new approaches for the treatment of CHF. This brief review focuses on data from preclinical experiments regarding the effects of increased adenylyl cyclase type 6 (AC6) expression on cellular and cardiac function, and possible mechanisms for the unexpected favorable effects of increased AC6 content on the failing heart.
Trends in Cardiovascular Medicine 11/2007; 17(7):215-21. DOI:10.1016/j.tcm.2007.07.001 · 2.91 Impact Factor
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