Deletion of the Acid-Sensing Ion Channel 1a Gene Leads to Age-Related Hypertension in Male but not Female Mice

Abstract

Acid-sensing ion channel 1a (ASIC1a) is a proton-gated cation channel that conducts both Na+ and Ca2+ in the cell. Studies have shown that ASIC1a is expressed in smooth muscle and endothelial cells of various vascular beds. Previously, we have shown that ASIC1a contributes to pulmonary hypertension and pulmonary arterial vasoconstrictor reactivity. Additionally, we recently discovered that inhibition of ASIC1a significantly reduced endothelial-dependent vasodilation in mesenteric arteries leading us to question whether ASIC1a contributes to the regulation of systemic mean arterial blood pressure (MABP). The incidences of cardiovascular disease are higher in males than females at a young age, however, this difference is largely diminished in post-menopausal females. Therefore, we aim to determine the age- and sex-related contribution of ASIC1a to cardiovascular homeostasis. We hypothesize that the genetic deletion of Asic1a will lead to age-related systemic hypertension in both male and female mice. MABP and heart rate (HR) were measured using radiotelemetry in conscious young (6-8 months) and aged (>15 months), male and female, Asic1a +/+ and Asic1a -/- mice. We found that Asic1a -/- male mice develop age-related systemic hypertension and increased HR compared to aged-matched Asic1a +/+ males. However, there were no differences in MABP in aged female mice and HR was significantly lower in Asic1a -/- mice compared to age-matched Asic1a +/+ mice (p=0.0008). To determine if Asic1a is contributing to age-induced systemic hypertension through a vascular or central regulation, norepinephrine and epinephrine levels were measured with an ELISA in young and aged Asic1a +/+ and Asic1a -/- mice. Although there was not a significant change in epinephrine between genotypes, norepinephrine was significantly increased in aged Asic1a -/- compared to young Asic1a -/- (p<0.0001) and aged-matched Asic1a +/+ (p<0.0001) mice indicating that the increased MABP is associated with elevated sympathetic nerve activity. Age increased norepinephrine levels in aged female mice, however, there was no statistical difference between genotypes. Together this data shows a sex-specific role for Asic1a to regulate age-induced systemic hypertension. Future studies will define the centrally-mediated mechanism by which Asic1a regulates MABP. Supported by National Heart, Lung, and Blood Institute Grants R01 HL-111084 to N.L. Jernigan and T32 HL-007736 to T.C. Resta This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.