Abstract 15299: TWIK-Related Acid-Sensitive K+ Channels Affect the Development of Aortic Root Aneurysms in Mice
Introduction: Aortic aneurysms are a significant cause of morbidity and mortality, yet the genetics underlying aortic aneurysm formation remain poorly understood. TWIK-related acid-sensitive K+ (TASK) channels are present in aortic tissue and important in neurohormonal regulation, but their function in the aorta is unknown.
Hypothesis: TASK-1 and TASK-3 channels affect aortic root morphology.
Methods: To investigate the involvement of TASK channels in thoracic aortic aneurysm development, TASK-1/3 double knockout (DKO), wild type (WT), and Marfan mice underwent serial echocardiography from 8 to 36 weeks of age to assess changes in aortic root diameter. In addition, aortic root histology was assessed in each cohort to evaluate aortic root architecture. Because TASK-1/3 DKO mice are known to have hyperaldosteronism, we tested whether aldosterone blockade with spironolactone affected aortic root diameter on serial echocardiography in TASK-1/3 DKO and WT mice.
Results: TASK-1/3 DKO mice showed significant aortic root dilation over time compared to WT on serial echocardiography (P<0.001). While Marfan mice had significant aortic root dilation at 8-12 weeks, the dilation in TASK-1/3 DKO mice occurred at 16-20 weeks of age. On histological assessment, both TASK-1/3 DKO and Marfan mice had thicker aortic root walls (P<0.05) and significant elastin fragmentation (P<0.001) compared to WT. TASK-1/3 DKO mice treated with spironolactone showed significant attenuation of the aortic root dilation, and at 28 weeks of age, aortic root diameter was similar to WT controls.
Conclusion: Loss of both TASK-1 and TASK-3 channels leads to spontaneous development of aortic root aneurysms that are associated with aortic root wall thickening and elastin disruption. Over time, aortic aneurysm formation in TASK-1/3 DKO mice closely mimics aneurysm formation in Marfan mice. Aldosterone blockade in TASK-1/3 DKO mice reduces aortic aneurysm formation, indicating a potential pathogenic role for aldosterone. These findings suggest that loss of function variants of TASK channels in humans may be important for the development of thoracic aortic aneurysms and raise the possibility of aldosterone blockade as a therapeutic option.
Author Disclosures: R.D. Torok: None. D.M. Abraham: None. C. Gareri: None. L. Mao: None. H.A. Rockman: None.
- © 2016 by American Heart Association, Inc.