Abstract 11285: Heart Failure Rescued by Pharmacological Inhibition of Type 5 Adenylyl Cyclase
Despite numerous discoveries from genetically engineered mice, relatively few have been translated to the bedside, mainly because it is difficult to disrupt or overexpress a gene in patients, whereas a drug is more amenable to therapy. We examined the extent to which a pharmacological inhibitor of type 5 adenylyl cyclase (AC5), Vidarabine, could mimic the salutary effects observed in the AC5 knockout model, which are mediated by the MEK-ERK pathway, and favorably affect the progression of heart failure (HF) in mice challenged with permanent coronary artery occlusion (CAO). The inhibitor was selective for AC5, i.e., it reduced AC activity significantly in AC5 transgenic mice, but not at all in AC5 knockout mice and had little effect in either wild type or AC6 transgenic mice. Permanent CAO for 3 weeks in mice treated with vehicle resulted in 69% mortality and reduced left ventricular (LV) ejection fraction (EF) (from 73.9±1 to 42±5 %), while increasing apoptosis to 0.31±0.02 % of total nuclei and cardiac fibrosis adjacent to the infarct to 42.3±2.3 % of total area. The AC5 inhibitor significantly improved these end points, p<0.05; mortality fell to 19 %; apoptosis fell to 0.19±0.02 % of total nuclei; fibrosis fell to 25.6±1.3 % of total area; while LVEF rose to 57±2 %. A traditional beta blocker, metoprolol, exerted salutary effects following permanent CAO similar to the AC5 inhibitor, except for fibrosis, which was not reduced (37.0±1.7 % of total area). To determine that the mechanism of the AC5 inhibitor was not simply due to beta blockade, we administered an acute isoproterenol challenge, where the increase in LVEF was blocked by metoprolol, but not by the AC5 inhibitor. Furthermore, co-administration of a MEK inhibitor, U0126, abolished the beneficial effects of the AC5 inhibitor, but not metoprolol, indicating the involvement of the MEK-ERK pathway. Thus, pharmacological AC5 inhibition may serve as a new therapeutic approach for HF, which works through a different mechanism than beta blockers and provides additional protection against the fibrosis associated with chronic myocardial infarction and remodeling.
- © 2010 by American Heart Association, Inc.