Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Oxidative Stress Research

Background:

• Cardiac pressure overload triggers adaptive hypertrophy, which can progress to maladaptive dilation and dysfunction.
• Reactive oxygen species (ROS) are implicated in the pathological remodeling of the heart under pressure load.

Purpose of the Study:

• To investigate the role of nitric oxide synthase-3 (NOS3) uncoupling in pressure overload-induced cardiac remodeling and dysfunction.
• To determine if targeting NOS3 uncoupling can ameliorate cardiac pathology.

Main Methods:

• Utilized chronic transverse aortic constriction (TAC) in wild-type and NOS3-deficient mice.
• Assessed cardiac hypertrophy, dilation, function, fibrosis, and fetal gene expression.
• Measured ROS production, nitrotyrosine levels, gelatinase activity, NOS3 dimer, and tetrahydrobiopterin (BH4) levels.
• Investigated the effect of BH4 cotreatment on TAC-induced cardiac changes.

Main Results:

• NOS3 deficiency attenuated TAC-induced cardiac hypertrophy, dilation, fibrosis, and dysfunction.
• TAC induced NOS3 uncoupling, characterized by reduced BH4 and dimer levels, and increased ROS generation.
• BH4 cotreatment prevented NOS3 uncoupling and ROS production, leading to preserved cardiac function and non-dilated hypertrophy.
• Antioxidant tetrahydroneopterin did not alter the TAC response.

Conclusions:

• NOS3 uncoupling is a significant source of myocardial ROS during pressure overload, driving dilatory remodeling and dysfunction.
• BH4 treatment effectively reverses NOS3 uncoupling and mitigates pressure overload-induced cardiac pathology, suggesting a therapeutic potential.