title: A Food and Drug Administration-Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion.
abstract: A Food and Drug Administration-approved antiviral agent, known as vidarabine or adenine 9-β-D-arabinofuranoside (AraA), has features of inhibiting adenylyl cyclase type 5 (AC5) and protects against chronic coronary artery occlusion (CAO). The goal of this investigation was to determine whether AraA protects against myocardial ischemia, even when delivered after coronary artery reperfusion (CAR). AraA, delivered after CAR in wild-type mice, reduced infarct size by 55% compared with vehicle-treated controls, whereas an equal dose of adenosine reduced infarct size only when administered before CAR. A 5-fold greater dose of adenosine was required to reduce infarct size when delivered after CAR, which also reduced arterial pressure by 15%, whereas AraA did not affect pressure. The reduction in infarct size with AraA was prevented by a MEK/extracellular signal-regulated kinase blocker, a pathway also involved in the mechanism of protection of the AC5 knockout (KO) model. Infarct size was also reduced in cardiac-specific AC5 KO mice similarly in the presence and absence of AraA, further suggesting that AraA protection involves the AC5 pathway. AraA reduced infarct size in chronically instrumented conscious pigs when delivered after CAR, and in this model, it also reduced post-CAR coronary hyperemia, which could be another mechanism for cardioprotection (i.e., by reducing oxidative stress during CAR). Thus, AraA inhibits AC5 and exhibits unique cardioprotection when delivered after CAR, which is critical for clinical translation.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Bravo
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey.
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey.
authors.forename: Ronald
authors.initials: R
authors.lastname: Pachon
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey vatnersf@njms.rutgers.edu.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D062186:Arterial Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003331:Coronary Vessels; D017277:Drug Approval; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000382:microbiology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D034421:Sus scrofa; D014481:United States; D014486:United States Food and Drug Administration; D014740:Vidarabine / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V; D014740:Vidarabine; D000241:Adenosine