A food and drug administration-approved antiviral agent that inhibits adenylyl cyclase type 5 protects the ischemic heart even when administered after reperfusion

Claudio A. Bravo, Dorothy E. Vatner, Ronald Pachon, Jie Zhang, Stephen F. Vatner

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9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)331-336
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume357
Issue number2
DOIs
StatePublished - May 2016

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Myocardial Reperfusion
United States Food and Drug Administration
Reperfusion
Antiviral Agents
Coronary Vessels
Adenosine
Vidarabine
adenylyl cyclase type V
Coronary Occlusion
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Hyperemia
Adenine
Knockout Mice
Myocardial Ischemia
Arterial Pressure
Oxidative Stress
Swine
Pressure

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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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.",
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AU - Zhang, Jie

AU - Vatner, Stephen F.

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