Isoproterenol-induced Cardiac Dysfunction in Male and Female C57Bl/6 Mice

Marianne K. O. Grant, Ibrahim Y. Abdelgawad, Christine A. Lewis, Davis Seelig, Beshay N. Zordoky
2020 · doi:10.1101/2020.04.17.046417
preprint OA: closed CC-BY-4.0
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This study found no significant sex-related differences in isoproterenol-induced cardiac hypertrophy, dysfunction, or fibrosis in male and female C57Bl/6 mice, with gonadectomy also showing no impact.

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Abstract

ABSTRACT Sex-related differences in cardiovascular diseases are complex and context-dependent. The objective of this work was to comprehensively determine key sex differences in the response to acute and chronic adrenergic stimulation in C57Bl/6 mice. Cardiac function was assessed by trans-thoracic echocardiography before and after acute adrenergic stimulation (a single sub-cutaneous dose of isoproterenol 10 mg/kg) in male and female C57Bl/6 mice. Thereafter, chronic adrenergic stimulation was achieved by sub-cutaneous injections of isoproterenol 10 mg/kg/day for 14 days in male and female mice. Cardiac function and morphometry were assessed by trans-thoracic echocardiography on the 15 th day. Thereafter, the mice were euthanized and the hearts were collected. Histopathological analysis of myocardial tissue was performed after staining with hematoxylin & eosin, trichrome, and MAC-2 antibody. Gene expression of remodeling and fibrotic markers was assessed by real-time PCR. Cardiac function and morphometry were also measured before and after isoproterenol 10 mg/kg/day for 14 days in groups of gonadectomized male and female mice and sham-operated controls. In the current work, there were no statistically significant differences in key echocardiographic parameters between male and female C57Bl/6 mice in response to acute adrenergic stimulation. After chronic adrenergic stimulation, there was similar degree of cardiac dysfunction, cardiac hypertrophy, and myocardial fibrosis in male and female mice. Similarly, chronic isoproterenol administration induced hypertrophic and fibrotic genes in hearts of male and female mice to the same extent. Intriguingly, gonadectomy of male and female mice did not have a significant impact on isoproterenol-induced cardiac dysfunction as compared to sham-operated animals. The current work demonstrated lack of significant sex-related differences in isoproterenol-induced cardiac hypertrophy, dysfunction, and fibrosis in C57Bl/6 mice. This study suggests that female sex may not be sufficient to protect the heart against a severe pathologic stimulus and underscores the notion that sexual dimorphism in cardiovascular diseases is highly model-dependent.

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License: CC-BY-4.0