Abstract 444: Absence of S100A1 in Mice is Associated With a Hypertensive Phenotype Dependent on Both Gender and Endothelial Function
Background: S100A1 is a small Ca2+-binding protein, expressed in myocardium and blood vessels, downregulated in diseased heart, and plays a significant role in regulating cardiac muscle Ca2+ homeostasis and contractility. While its expression level in endothelial and smooth muscle cells is increased during arterial vasospasm, little is known about its physiological role in the vasculature.
Methods and results: In a knockout (KO) mouse model, we examined the effect of S100A1 deficiency on systemic blood pressure in vivo and vascular function in isolated blood vessel preparations. Hemodynamic comparison by Millar catheter revealed higher mean arterial pressure (MAP) in KO mice compared to wild-type (WT) controls ( 84 ± 1 vs. 69 ± 1 mmHg, P<0.001; n=28–31). Male KO mice exhibited higher MAP compared to female KO mice (87 ± 1 vs. 78 ± 2 mmHg, P<0.001; n=8–20). Interestingly, this mild hypertension observed in male KO was sufficient to induce cardiac hypertrophy when compared to WT (Heart/Body Weight ratio 4.3 ± 0.1 vs. 4.1 ± 0.1, P<0.05; n=14–17). Moreover, acute hemodynamic comparison revealed a paradoxical increase in left ventricular systolic pressure (LVSP) in male KO mice, and a characteristic decrease in female KO, following intraperitoneal injection of the alpha2-adrenergic agonist, xylazine (20mg/kg), when compared to WT (ΔLVSP: +31 ± 0.1 vs. -18 ± 2 mmHg, P<0.001; n=3). In phenylephrine-preconstricted isolated aortas and mesenteric arteries, acetylcholine-induced vasodilation in male KO was significantly reduced compared to male WT (p<0.05, n=5). Using specific antibodies, immunohistochemistry demonstrated expression of S100A1 in cultured human aortic endothelial cells (HAEC) and co-localization with endothelial nitric oxide synthase (eNOS). In agreement, S100A1 also specifically co-immunoprecipitated with eNOS.
Conclusions: Our data suggest that S100A1 plays a crucial role in regulation of basal blood pressure in a gender-specific manner. S100A1 and eNOS are colocalized in endothelial cells and regulation of blood pressure by S100A1 appears to be mediated by endothelial function. Thus, expression of S100A1 may be important in the coordinate regulation of both myocardial and vascular function in health and disease.