Abstract 038: The Arg16 / Gln27 Diplotype of the Beta-2 Adrenergic Receptor: Cardiovascular Insights from a Novel Transgenic Mouse Model

Abstract

Listen

Translate article

The beta-2 adrenergic receptor (B2AR) is an established regulator of vascular tone and cardiac contractility. Two polymorphisms of the B2AR (Gly16Arg and Glu27Gln) have been associated with cardiovascular phenotypes, including hypertension, salt sensitivity of BP, cardiovascular disease and responses to antihypertensives. These same variants are associated with changes in receptor downregulation and desensitization in pulmonary tissues; however, there is no information on the effect of these polymorphisms on B2AR expression/function in cardiovascular tissues. To investigate the effect of these variants on cardiovascular function, we used the CRISPR/Cas9 approach to generate transgenic mice that carry the diplotype Arg16/Gln27 on 2, 1 or 0 alleles, i. e. mutant (Mut), heterozygous (Het) and wild-type (WT). Both male and female mice displayed significantly higher body weights with the increase in number of mutated alleles (P<0.05). Systolic and diastolic BP showed a similar positive dose-response relationship with the number of mutated alleles, irrespective of the gender (P(trend) < 0.001). In contrast, pulse pressure and heart rates were not significantly affected by the diplotype. Urine and plasma aldosterone levels (but not plasma renin activity) were progressively downregulated in the male but not female carriers of the diplotype (P<0.01). Cardiac ultrasound measurements revealed that male diplotype carriers displayed a decrease in left ventricular wall thickness, especially during systole (P<0.05), with a corresponding increase in internal diameter and volume, decreased stroke volume and fractional shortening (P<0.05); however, there were no significant effects of diplotype in the females. Cardiac B2AR transcript levels were significantly decreased in male but not female diplotype carriers versus WT. Our study provides strong support for a direct sex-dependent effect of the Arg16/Gln27 diplotype on cardiovascular function and supports the translational value of our novel animal model.