Cardioprotective Effects of Beta3-Adrenergic Receptor (β3-AR) Pre-, Per-, and Post-treatment in Ischemia–Reperfusion

Autor: Aisha Khlani Hassan Alsalhin, Ruduwaan Salie, Amanda Lochner, Erna Marais
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Agonist
Time Factors
Nitric Oxide Synthase Type III
medicine.drug_class
Myocardial Infarction
Adrenergic beta-3 Receptor Agonists
Myocardial Reperfusion Injury
030204 cardiovascular system & hematology
Pharmacology
Nitric Oxide
Nitric oxide
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Enos
medicine
Animals
Myocytes
Cardiac
Pharmacology (medical)
Phosphorylation
Rats
Wistar
Extracellular Signal-Regulated MAP Kinases
Receptor
Cyclic GMP
Protein kinase B
Cardioprotection
Glycogen Synthase Kinase 3 beta
biology
business.industry
Hemodynamics
Antagonist
Isolated Heart Preparation
General Medicine
medicine.disease
biology.organism_classification
Disease Models
Animal
030104 developmental biology
chemistry
Receptors
Adrenergic
beta-3
Adrenergic beta-3 Receptor Antagonists
Cardiology and Cardiovascular Medicine
business
Reperfusion injury
Signal Transduction
Zdroj: Cardiovascular Drugs and Therapy. 33:163-177
ISSN: 1573-7241
0920-3206
Popis: The β3-AR (beta3-adrenergic receptor) is resistant to short-term agonist-promoted desensitization and delivers a constant intracellular signal, making this receptor a potential target in acute myocardial infarction (AMI). To investigate whether selective modulation of β3-AR prior to or during ischemia and/or reperfusion may be cardioprotective. Isolated perfused rat hearts were exposed to 35-min regional ischemia (RI) and 60-min reperfusion. The β3-AR agonist (BRL37344, 1 μM) or antagonist (SR59230A, 0.1 μM) was applied: (i) before RI (PreT) or (ii) last 10 min of RI (PerT) or (iii) onset of reperfusion (PostT) or (iv) during both PerT+PostT. Nitric oxide (NO) involvement was assessed, using the NOS inhibitor, L-NAME (50 μM). Endpoints were functional recovery, infarct size (IS), cGMP levels, and Western blot analysis of eNOS, ERKp44/p42, PKB/Akt, and glycogen synthase kinase-3β (GSK-3β). Selective treatment with BRL significantly reduced IS. L-NAME abolished BRL-mediated cardioprotection. BRL (PreT) and BRL (PerT) significantly increased cGMP levels (which were reduced by L-NAME) and PKB/Akt phosphorylation. BRL (PostT) produced significantly increased cGMP levels, PKB/Akt, and ERKp44/p42 phosphorylation. BRL (PerT+PostT) caused significant eNOS, PKB/Akt, ERKp44/p42, and GSK-3β phosphorylation. β3-AR activation by BRL37344 induced significant cardioprotection regardless of the experimental protocol. However, the pattern of intracellular signaling with each BRL treatment differed to some degree and suggests the involvement of cGMP, eNOS, ERK, GSK-3β, and particularly PKB/Akt activation. The data also suggest that clinical application of β3-AR stimulation should preferably be incorporated during late ischemia or/and early reperfusion.
Databáze: OpenAIRE
Externí odkaz: