β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes

Basic Res Cardiol. 2014 Jul;109(4):422. doi: 10.1007/s00395-014-0422-0. Epub 2014 Jun 21.

Abstract

Selective stimulation of β3 adrenergic-receptor (β3AR) has been shown to reduce infarct size in a mouse model of myocardial ischemia/reperfusion. However, its functional long-term effect and the cardioprotective mechanisms at the level of cardiomyocytes have not been elucidated, and the impact of β3AR stimulation has not been evaluated in a more translational large animal model. This study aimed at evaluating pre-perfusion administration of BRL37344 both in small and large animal models of myocardial ischemia/reperfusion. Pre-reperfusion administration of the β3AR agonist BRL37344 (5 μg/kg) reduced infarct size at 2-and 24-h reperfusion in wild-type mice. Long-term (12-weeks) left ventricular (LV) function assessed by echocardiography and cardiac magnetic resonance (CMR) was significantly improved in β3AR agonist-treated mice. Incubation with β3AR agonist (BRL37344, 7 μmol/L) significantly reduced cell death in isolated adult mouse cardiomyocytes during hypoxia/reoxygenation and decreased susceptibility to deleterious opening of the mitochondrial permeability transition pore (mPTP), via a mechanism dependent on the Akt-NO signaling pathway. Pre-reperfusion BRL37344 administration had no effect on infarct size in cyclophilin-D KO mice, further implicating mPTP in the mechanism of protection. Large-white pigs underwent percutaneous coronary ischemia/reperfusion and 3-T CMR at 7 and 45 days post-infarction. Pre-perfusion administration of BRL37344 (5 μg/kg) decreased infarct size and improved long-term LV contractile function. A single-dose administration of β3AR agonist before reperfusion decreased infarct size and resulted in a consistent and long-term improvement in cardiac function, both in small and large animal models of myocardial ischemia/reperfusion. This protection appears to be executed through inhibition of mPTP opening in cardiomyocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-3 Receptor Agonists / pharmacology*
  • Animals
  • Cardiotonic Agents / pharmacology*
  • Cell Death / drug effects
  • Cyclophilin D
  • Cyclophilins / deficiency
  • Cyclophilins / genetics
  • Disease Models, Animal
  • Ethanolamines / pharmacology*
  • Magnetic Resonance Imaging
  • Male
  • Mice, Knockout
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Nitric Oxide / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Adrenergic, beta-3 / drug effects*
  • Receptors, Adrenergic, beta-3 / metabolism
  • Signal Transduction / drug effects
  • Swine
  • Time Factors
  • Ventricular Function, Left / drug effects*

Substances

  • Adrenergic beta-3 Receptor Agonists
  • Cardiotonic Agents
  • Cyclophilin D
  • Ethanolamines
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • PPIF protein, mouse
  • Receptors, Adrenergic, beta-3
  • Nitric Oxide
  • BRL 37344
  • Proto-Oncogene Proteins c-akt
  • Cyclophilins