Abstract 20884: TWIK-2 Deficient Mice are Hypertensive and Exhibit Greater Vascular Contractility
TWIK-2, a member of the Two-Pore Domain K+ ion channel family, is highly expressed in the vascular system; however its function is unknown. We hypothesized that TWIK-2 is involved with regulating vascular tone in arteries. Mice lacking TWIK-2 (KO) were generated by deleting exon 2 of KCNK6, which encodes the first pore region of the TWIK-2 protein. Male KO and littermate wild type (WT) mice between 8 and 12 weeks were used in these studies. Systolic and mean arterial blood pressure, but not diastolic blood pressure, were significantly increased in pentobarbital anesthetized mice (n=6 pairs) [systolic 115.4 mmHg +/− 6.5 and 98.1 mmHg +/− 3.1 in KO and WT respectively (p=0.038); mean arterial pressures 98.2 mmHg +/− 6.0 and 80.9 mmHg +/− 4.1 in KO and WT respectively (p=0.039); and diastolic 80.2 mmHg +/− 5.4 and 64.1 mmHg +/− 5.0 in KO and WT respectively (p=0.054)]. Isolated segments of thoracic aorta were evaluated by wire myography. Force generated by addition of KCl (40 to 120 mM) was significantly greater in aortic segments from KO compared to those of WT (n=6, p=0.035, 2 way repeated measures ANOVA). For example aortic segments from KO mice contracted 54% +/−12 greater than segments from WT mice to 60 mM KCl (p=0.008). Nifedipine, a selective L-type calcium channel blocker, reversed the contractile effects of 60 mM KCl in a dose -dependent manner with no difference between the genotype (n=4 pairs). The L-type calcium channel agonist, BayK 8644 (10−9 to 10−6 M), contracted aortic segments from both WT and KO mice; however, the KO showed a more pronounced contraction (p=0.042, n=5 pairs, 2 way repeated measures ANOVA). For example, at 10−6 M the KO segment constricted 67% +/−10 more than the WT segment (p<0.001). Nifedipine reversed the contractile response in segments from both genotypes in a dose dependent manner (n=4 pairs). We conclude that the KCl constriction was acting via L-type Ca channels. In summary, TWIK-2 deficiency is sufficient to induce moderate hypertension in the KO mouse, potentially through enhancing a contractile phenotype in arteries. TWIK-2 channels apparently have an important influence on L-type calcium channels either directly by modulating their activity or indirectly by modulating the membrane potential of vascular smooth muscle.
- © 2010 by American Heart Association, Inc.