Dietary potassium regulates vascular calcification and arterial stiffness
Yong Sun, Chang Hyun Byon, Youfeng Yang, Wayne E. Bradley, Louis J. Dell’Italia, Paul W. Sanders, Anupam Agarwal, Hui Wu, Yabing Chen
Yong Sun, Chang Hyun Byon, Youfeng Yang, Wayne E. Bradley, Louis J. Dell’Italia, Paul W. Sanders, Anupam Agarwal, Hui Wu, Yabing Chen
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Research Article Vascular biology

Dietary potassium regulates vascular calcification and arterial stiffness

Abstract

Vascular calcification is a risk factor that predicts adverse cardiovascular complications of several diseases including atherosclerosis. Reduced dietary potassium intake has been linked to cardiovascular diseases such as hypertension and incidental stroke, although the underlying molecular mechanisms remain largely unknown. Using the ApoE-deficient mouse model, we demonstrated for the first time to our knowledge that reduced dietary potassium (0.3%) promoted atherosclerotic vascular calcification and increased aortic stiffness, compared with normal (0.7%) potassium–fed mice. In contrast, increased dietary potassium (2.1%) attenuated vascular calcification and aortic stiffness. Mechanistically, reduction in the potassium concentration to the lower limit of the physiological range increased intracellular calcium, which activated a cAMP response element–binding protein (CREB) signal that subsequently enhanced autophagy and promoted vascular smooth muscle cell (VSMC) calcification. Inhibition of calcium signals and knockdown of either CREB or ATG7, an autophagy regulator, attenuated VSMC calcification induced by low potassium. Consistently, elevated autophagy and CREB signaling were demonstrated in the calcified arteries from low potassium diet–fed mice as well as aortic arteries exposed to low potassium ex vivo. These studies established a potentially novel causative role of dietary potassium intake in regulating atherosclerotic vascular calcification and stiffness, and uncovered mechanisms that offer opportunities to develop therapeutic strategies to control vascular disease.

Authors

Yong Sun, Chang Hyun Byon, Youfeng Yang, Wayne E. Bradley, Louis J. Dell’Italia, Paul W. Sanders, Anupam Agarwal, Hui Wu, Yabing Chen

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Figure 6

Potassium regulated the activation of CREB and autophagy in vascular calcification ex vivo and in vivo.

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Potassium regulated the activation of CREB and autophagy in vascular cal...
(A) Effects of low potassium on the activation of calcium-activated cAMP response element–binding protein (CREB) and autophagy signals ex vivo. Aortic rings from wild-type mice were exposed to osteogenic media with control (5.4 mM), low potassium (3.7 mM, Low K+), or high potassium (6.0 mM, High K+) for 3 weeks. Western blot analysis was performed to determine the phosphorylation of protein kinase C (PKC), CREB, and the expression of microtubule-associated protein 1 light chain 3 (LC3) and runt-related transcription factor 2 (Runx2). Representative blots from 3 independent experiments are shown. (B) Effects of dietary potassium on the activation of CREB and autophagy signals in vivo. Western blot analysis was performed to determine the phosphorylation of PKC, CREB and the expression of LC3 and Runx2 in descending aortas of control, low, or high potassium diet–fed mice. Representative Western blot analyses of protein lysates extracted from the descending aortas from at least 3 mice in each group are shown. (C) Schematic illustration of vascular calcification regulated by potassium. Low potassium activates calcium signaling that promotes activation of CREB, which results in chronically excessive autophagy in vascular smooth muscle cells (VSMCs), leading to the development of calcification. High potassium reverses vascular calcification.