Contractile Function During Angiotensin-II Activation

Autor: Alison C. Brewer, Antonio Nei Santana Gondim, Alessandra Ghigo, Celio X.C. Santos, Moradeke A. Bamboye, W. Jonathan Lederer, Christopher W. Ward, Ajay M. Shah, Alessia Perino, Min Zhang, Emilio Hirsch, Daniel Martin, Benjamin L. Prosser
Rok vydání: 2015
Předmět:
Ryanodine receptor 2
HF
heart failure
Muscle hypertrophy
NADPH
reduced nicotinamide adenine dinucleotide phosphate
Renin-Angiotensin System
Mice
Medicine
Myocytes
Cardiac
Phosphorylation
Original Investigation
myocyte
NADPH oxidase
Membrane Glycoproteins
biology
Angiotensin II
Models
Cardiovascular
Phospholamban
PP1
protein phosphatase 1
RyR2
ryanodine receptor
Sarcoplasmic Reticulum
Cardiovascular Diseases
NADPH Oxidase 2
cardiovascular system
Cardiology and Cardiovascular Medicine
hormones
hormone substitutes
and hormone antagonists
medicine.medical_specialty
SERCA
Mice
Transgenic
Contractility
ROS
reactive oxygen species
Internal medicine
Animals
[Ca2+]i
intracellular calcium ions
LV
left ventricular
Pressure overload
Ang II
angiotensin II
NCX
sodium-calcium exchange
business.industry
Calcium-Binding Proteins
contraction
NADPH Oxidases
RAS
renin-angiotensin system
SR
sarcoplasmic reticulum
Myocardial Contraction
Disease Models
Animal
Endocrinology
biology.protein
Nox2
NADPH oxidase 2
PKA
protein kinase A
Calcium
business
Reactive Oxygen Species
SERCA
sarcoplasmic reticulum Ca2+-ATPase
Zdroj: Journal of the American College of Cardiology
ISSN: 0735-1097
DOI: 10.1016/j.jacc.2015.05.020
Popis: Background Renin-angiotensin system activation is a feature of many cardiovascular conditions. Activity of myocardial reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2 or Nox2) is enhanced by angiotensin II (Ang II) and contributes to increased hypertrophy, fibrosis, and adverse remodeling. Recent studies found that Nox2-mediated reactive oxygen species production modulates physiological cardiomyocyte function. Objectives This study sought to investigate the effects of cardiomyocyte Nox2 on contractile function during increased Ang II activation. Methods We generated a cardiomyocyte-targeted Nox2-transgenic mouse model and studied the effects of in vivo and ex vivo Ang II stimulation, as well as chronic aortic banding. Results Chronic subpressor Ang II infusion induced greater cardiac hypertrophy in transgenic than wild-type mice but unexpectedly enhanced contractile function. Acute Ang II treatment also enhanced contractile function in transgenic hearts in vivo and transgenic cardiomyocytes ex vivo. Ang II–stimulated Nox2 activity increased sarcoplasmic reticulum (SR) Ca 2+ uptake in transgenic mice, increased the Ca 2+ transient and contractile amplitude, and accelerated cardiomyocyte contraction and relaxation. Elevated Nox2 activity increased phospholamban phosphorylation in both hearts and cardiomyocytes, related to inhibition of protein phosphatase 1 activity. In a model of aortic banding–induced chronic pressure overload, heart function was similarly depressed in transgenic and wild-type mice. Conclusions We identified a novel mechanism in which Nox2 modulates cardiomyocyte SR Ca 2+ uptake and contractile function through redox-regulated changes in phospholamban phosphorylation. This mechanism can drive increased contractility in the short term in disease states characterized by enhanced renin-angiotensin system activation.
Databáze: OpenAIRE
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