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Published on: October 3, 2019
Myocardial oxidative stress contributes to transgenic β₂-adrenoceptor activation-induced cardiomyopathy and heart
1Baker IDI Heart and Diabetes Institute, Melbourne, Australia. qi.xu@bakeridi.edu.au
Background And Purpose:
While maintaining cardiac performance, chronic β-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic β₂-adrenoceptor activation.
Experimental Approach:
Mice with transgenic β₂-adrenoceptor overexpression (β₂-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared.
Key Results:
β₂-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. β₂-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of β₂-TG mice. NAC treatment (500 mg·kg⁻¹ ·day⁻¹) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of β₂-TG mice. Chronic NAC treatment to β₂-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 ± 5% vs. 25 ± 3%, ejection fraction 52 ± 5% vs. 32 ± 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity.
Conclusion And Implications:
β₂-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure.
Insights
Chronic beta-2 adrenoceptor activation in mice leads to heart failure via increased reactive oxygen species (ROS) and inflammation. Antioxidant treatment with N-acetylcysteine (NAC) mitigated these effects, preserving cardiac function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Pharmacology
Background:
- Chronic beta-2 adrenoceptor activation can worsen cardiac remodeling and failure.
- The role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) in this process requires further investigation.
Purpose of the Study:
- To investigate the signaling pathways involving NADPH oxidase and ROS in chronic beta-2 adrenoceptor activation.
- To assess the therapeutic potential of antioxidants and NADPH oxidase inhibitors in mitigating adverse cardiac remodeling.
Main Methods:
- Utilized transgenic mice overexpressing beta-2 adrenoceptors (beta-2 TG) and non-transgenic littermates.
- Administered antioxidants (N-acetylcysteine, NAC) and NADPH oxidase inhibitors (apocynin, diphenyliodonium).
- Measured ROS levels, p38 MAPK phosphorylation, inflammatory cytokines, collagen content, and left ventricular (LV) function.
Main Results:
- Beta-2 TG mice exhibited increased ROS, p38 MAPK and HSP27 phosphorylation, inflammation, collagen deposition, and ventricular dysfunction.
- NAC and NADPH oxidase inhibitors reduced p38 MAPK and HSP27 phosphorylation in cardiomyocytes and LV tissue.
- Chronic NAC treatment prevented ventricular dilation, preserved cardiac function, reduced fibrosis, and suppressed matrix metalloproteinase activity in beta-2 TG mice.
Conclusions:
- Beta-2 adrenoceptor stimulation induces NADPH oxidase-dependent ROS production in the heart.
- Elevated ROS activate p38 MAPK, contributing to cardiac inflammation, remodeling, and failure.
- Targeting ROS with antioxidants like NAC shows promise in preventing beta-2 adrenoceptor-induced heart dysfunction.
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