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Dietary potassium regulates vascular calcification and arterial stiffness
Yong Sun, … , Hui Wu, Yabing Chen
Yong Sun, … , Hui Wu, Yabing Chen
Published October 5, 2017
Citation Information: JCI Insight. 2017;2(19):e94920. https://doi.org/10.1172/jci.insight.94920.
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Research Article Vascular biology

Dietary potassium regulates vascular calcification and arterial stiffness

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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 5

Low potassium promoted VSMC calcification through autophagy.

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Low potassium promoted VSMC calcification through autophagy.
(A) Effects...
(A) Effects of potassium concentrations on autophagy in vascular smooth muscle cells (VSMCs). VSMCs were cultured in osteogenic media with increased concentrations of potassium for 3 weeks. Western blot analysis was performed to determine the expression of the autophagic marker, microtubule-associated protein 1 light chain 3 (LC3), in the cytoplasmic form (LC3 I) and conjugated form (LC3 II). Representative blots from 3 independent experiments are shown. (B) Quantitative analysis of the LC3 II/I ratio in A, by densitometric analysis using ImageJ software. Bar values are means ± SD (n = 3, *P < 0.05 compared with potassium at 5.4 mM). Statistical analysis was performed by 1-way ANOVA followed by a Student-Newman-Keuls test. (C) Effects of inhibition of autophagy on low-potassium-induced VSMC calcification. VSMCs were exposed to osteogenic media with control or low potassium for 3 weeks, with or without the autophagy inhibitor, 3-methyladenine (3-MA). Calcification was determined by Alizarin red staining. (D) Effects of 3-MA on autophagy markers. Western blot analysis was used to determine LC3 I and II levels in C. Representative blots from 3 independent experiments are shown. (E) Effects of knockdown of autophagy-related 7 protein (ATG7) on low-potassium-induced VSMC calcification. VSMCs with ATG7 stably knocked down by shRNA (shATG7) or with control shRNA (shScr) were exposed to osteogenic media with control or low potassium for 3 weeks. Calcification was determined by Alizarin red staining. (F) Effects of ATG7 knockdown on autophagy markers. Western blot analysis was used to determine ATG7 and LC3 I and II levels in E. Representative results from 3 independent experiments are shown.

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