SUN-LB91 The Arg16/Gln27 Polymorphism of the Beta2-Adrenergic Receptor Impacts Blood Pressure Levels in a Transgenic Mouse Model via Sex-Specific Mechanisms

Background: The β2-adrenergic receptor (β2-AR) has been implicated in blood pressure (BP) homeostasis via its effects on the sympathetic nervous system, cardiac function, peripheral vascular resistance, and renin release. We also have documented that a β2-AR diplotype (Arg16/Gln27), carried by 15% of hypertensives, have salt sensitive hypertension (SSBP) and increased aldosterone (ALDO). Gap in knowledge: it has been reported that hypertensive men and women respond differently to beta blockers. However, information regarding sex differences in carriers of the β2-AR risk diplotype is limited. Hypothesis: In mice, the phenotype in female carriers of the mutant β2-AR risk diplotype will differ from male carriers. Methods: The CRISPR/Cas9 approach was used to generate transgenic mice carrying 0, 1 or 2 Arg16/Gln27 variant alleles (i.e. wild-type (WT), heterozygous (Het) or mutant (Mut)). The experimental design included twelve weeks old mice divided into 6 genotype/gender groups (male and female; WT, Het and Mut) maintained on low (0.03% Na+, LS) and high sodium diets (1.6% Na+, HS) for a week each. Results: 1) Both male and female mice displayed significantly increased BP on LS and HS with increasing number of mutated alleles. 2) Only Mut females displayed SSBP (P<0.05). 3) As compared to WT, urine and plasma ALDO levels were lower in male (but not female) carriers of the mutated allele (P<0.05). 4) As anticipated, urine K(+) excretion was significantly lower in the Mut male (but not female) mice (P<0.05). 5) Doppler ultrasound measurements of renovascular function shows that the resistive index was significantly lower in Mut vs WT males (P<0.05), consistent with an appropriate increase in renal blood flow (RBF) in the face of an elevated BP. However, in the Mut females the RBF was inappropriately decreased compared to the WT (P<0.05). 6) β2-AR expression was significantly lower in female vs. male WT mice; however, this difference was lost in the carriers of the mutated allele, as B2-AR expression levels were significantly higher in female carriers of the mutated allele, as compared to WT (P<0.05). Interestingly, the B2-AR genotype had no effect on the receptor expression levels in males. Conclusion: Both male and female Mut animals have increased BP compared to WT mice, but the mechanisms underlying their increased BP differ by sex. Female Mut mice have SSBP, inappropriately non-suppressed ALDO and decreased RBF. Male Mut mice do not have SSBP and have appropriate ALDO and RBF response to the salt load.