title: Effects of cardiac overexpression of type 6 adenylyl cyclase affects on the response to chronic pressure overload.
abstract: Adenylyl cyclase (AC) type 5 (AC5) and AC type 6 (AC6) are the two major AC isoforms in the heart. Cardiac overexpression of AC6 has been shown to be protective in response to several interventions. In this investigation, we examined the effects of chronic pressure overload in AC6 transgenic (TG) mice. In the absence of any stress, AC6 TG mice exhibited enhanced contractile function compared with their wild-type (WT) littermates, i.e., increased (P < 0.05) left ventricular (LV) ejection fraction (EF) (75 +/- 0.9 vs. 71 +/- 0.5%) and LV dP/dt (7,850 +/- 526 vs. 6,374 +/- 315 mmHg/s). Forskolin (25 microg x kg(-1) x min(-1) for 5 min) increased LVEF more (P < 0.05) in AC6 TG mice (14.8 +/- 1.0%) than in WT mice (7.7 +/- 1.0%). Also, isoproterenol (0.04 microg x kg(-1) x min(-1) for 5 min) increased LVEF more (P < 0.05) in AC6 TG mice (18.0 +/- 1.2%) than in WT mice (11.6 +/- 2.1%). Pressure overload, induced by 4 wk of transverse aortic constriction (TAC), increased the LV weight-to-body weight ratio and myocyte cross-sectional area similarly in both groups, but reduced LVEF more in AC6 TG mice (22%) compared with WT mice (9%), despite the higher starting level of LVEF in AC6 TG mice. LV systolic wall stress increased more in AC6 TG mice than in WT mice, which could be responsible for the reduced LVEF in AC6 TG mice with chronic pressure overload. In addition, LV dP/dt was no longer elevated in AC6 TG mice after TAC compared with WT mice. LV end-diastolic diameter was also greater (P < 0.05) in AC6 TG mice (3.8 +/- 0.07 mm) than in WT mice (3.6 +/- 0.05 mm) after TAC. Thus, in contrast to other interventions previously reported to be salutary with cardiac AC6 overpression, the response to chronic pressure overload was not; actually, AC6 TG mice fared worse than WT mice. The mechanism may be due to the increased LV systolic wall stress in AC6 TG mice with chronic pressure overload.
authors.affiliation: Department of Cell Biology and Molecular Medicine and Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Aziz
authors.initials: A
authors.lastname: Guellich
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Chull
authors.initials: C
authors.lastname: Hong
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wagner
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Dhar
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
authors.forename: Luc
authors.initials: L
authors.lastname: Hittinger
authors.forename: Kosaku
authors.initials: K
authors.lastname: Iwatsubo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D004452:Echocardiography; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000503:physiopathology; D007545:Isoproterenol; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D005576:Colforsin; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D007545:Isoproterenol