Abstract 5395: Pharmacological Inhibition of Type 5 Adenylyl Cyclase Attenuates Functional Deterioration in Chronic Catecholamine Stress
Type 5 adenylyl cyclase (AC5) null mice exhibit prolonged longevity and are resistant to development of heart failure (HF) following cardiac overload. An important mechanism mediating these salutary effects involves ERK-MEK signaling, a major cell survival pathway. To move from the bench to the bedside, we screened commercially available drugs for AC5 inhibition, and found that vidarabine, which was designed as an anti-viral drug, showed potent AC5 inhibition. We first determined that this drug inhibited AC5 specifically and did not inhibit AC6, the other major cardiac isoform. When IC50s in cAMP production in heart samples were compared among wild type (WT) mice, mice with cardiac specific overexpression of type 5 AC (AC5 Tg) and AC6 Tg, IC50 for AC5 Tg was significantly lower than that for WT while that for AC6 Tg was significantly higher (WT, 46.7±6 microM; AC5 Tg, 13.9±1 microM, p<0.01 vs. WT; AC6 Tg, 70.2±11 microM, p<0.01 vs. WT, n=4), suggesting that vidarabine is a selective AC5 inhibitor without AC6 inhibition. We next examined the effect of vidarabine on HF induced by chronic beta-adrenergic receptor stimulation with isoproterenol (ISO) in mice. After 1-week infusion of ISO (60 mg/kg/day) without vidarabine, left ventricular ejection fraction (LVEF) fell, p<0.05, to 56±8% compared with vehicle (74±2.3%), and induced a 5-fold increase in cardiac myocyte apoptosis (vehicle, 0.05±0.02%; ISO, 0.25±0.07%). Vidarabine prevented the decline in LVEF with chronic ISO (70.5±4.6%) and the increase in myocyte apoptosis (0.12±0.03%). Immunoblot analysis showed that vidarabine activated the ERK-MEK signaling pathway, similar to what was observed in AC5 null mice, suggesting that vidarabine reduced cardiac myocyte apoptosis and protected the heart via activating the ERK-MEK pathway. Thus, pharmacological inhibition of AC5 is feasible, and protects the heart following chronic catecholamine stress, suggesting this approach may serve as a new therapeutic modality for treating HF.