Heterozygous alpha 2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction

Area of Science:

• Cardiovascular Physiology
• Neuroendocrinology
• Adrenergic Signaling

Background:

• Feedback regulation of norepinephrine is crucial for cardiovascular homeostasis.
• Alpha(2C)-adrenoceptors are implicated in controlling epinephrine release from the adrenal medulla.
• Human alpha(2C)-adrenoceptor gene polymorphisms are linked to hypertension and heart failure.

Purpose of the Study:

• To investigate the role of alpha(2C)-adrenoceptor gene copy number in regulating epinephrine release.
• To assess the impact of alpha(2C)-adrenoceptor deficiency on cardiovascular function and heart failure susceptibility.

Main Methods:

• Compared adrenal catecholamine release, hemodynamics, and heart failure development in mice with two, one, or zero functional alpha(2C)-adrenoceptor genes.
• Utilized gene-targeted mice models (alpha(2C)+/+, alpha(2C)+/-, alpha(2C)-/-).
• Assessed urinary epinephrine excretion and telemetric cardiovascular parameters.

Main Results:

• Alpha(2C)+/- mice showed reduced alpha(2C) mRNA and impaired alpha(2)-receptor-mediated inhibition of catecholamine release.
• Urinary epinephrine excretion was significantly elevated in alpha(2C)+/- and alpha(2C)-/- mice.
• Alpha(2C)-deficient mice exhibited tachycardia and increased susceptibility to cardiac hypertrophy, failure, and mortality post-pressure overload.

Conclusions:

• Adrenal alpha(2)-mediated feedback of epinephrine secretion differs from sympathetic feedback.
• A single alpha(2C)-adrenoceptor subtype is critical for preventing elevated circulating epinephrine levels.
• This genetic model offers insights into alpha(2C)-adrenoceptor dysfunction in human cardiovascular pathophysiology.