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Adenylyl Cyclase Gene Transfer Increases Cardiac Function in Murine Cardiomyopathy
Author(s) -
Rebolledo Brian,
Lai Ngai Chin,
Takahashi Toshiyuki,
Roth David M.,
Hammond H. Kirk
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1189-b
Subject(s) - adenylyl cyclase , heart failure , medicine , cardiac function curve , dobutamine , basal (medicine) , endocrinology , cardiomyopathy , cardiology , in vivo , diastole , dilated cardiomyopathy , myocyte , ex vivo , biology , stimulation , hemodynamics , blood pressure , microbiology and biotechnology , insulin
Background Cardiac expression of Gαq results in heart failure (HF), and crossing Gαq mice and mice with cardiac expression of adenylyl cyclase VI (AC VI ) prevents HF. However, this does not indicate that AC VI is useful to treat HF for two reasons: 1) HF was prevented , not treated; 2) transgenic lines express high levels of the gene in all cardiac myocytes—impossible to replicate in clinical settings. Here we ask whether intracoronary delivery of an adenovirus encoding AC VI (Ad.AC VI ) would increase LV function in Gαq mice with active HF. Methods and Results Before treatment, Gαq mice showed reduced fractional area change (echocardiography) (Gαq: 25±12%; Con: 42±12%; n=8 both groups; p<0.012), increased LV end‐diastolic dimension (Gαq: 4.2±0.1 mm; Con: 3.2±0.4 mm; n=8 both groups; p<0.0001) and exercise duration was reduced (Gαq: 399±23 s, n=5; Con: 509±68 s, n=7; p<0.007). Gαq mice then received 2.5x10 10 vp of Ad.AC VI (n=10) or Ad.EGFP (enhanced green fluorescent protein, n=10) via intracoronary gene delivery in a blinded study; 14d later LV dP/dt in response to dobutamine (1–30 μmol/l) was measured in isolated perfused hearts. Gαq mice that received Ad.AC VI showed increased LV +dP/dt and –dP/dt compared to Gαq mice that received Ad.EGFP (p<0.0001) ( Figure ). Basal heart rates in the ex‐vivo setting were similar (Ad.AC VI : 234±33 bpm; Ad.EGFP: 218±55 bpm; n=10 both groups; p=0.44).Conclusion Intracoronary delivery of AC VI increases cardiac function in mice with heart failure. This research was supported by NHLBI Minority Research Supplement.