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.
View: Text | PDF
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

×

Figure 4

Activation of calcium signaling–mediated CREB was required for low-potassium-induced VSMC calcification.

Options: View larger image (or click on image) Download as PowerPoint
Activation of calcium signaling–mediated CREB was required for low-potas...
(A) Effects of potassium levels on intracellular calcium, determined by Fluo4 NW, in vascular smooth muscle cells (VSMCs) exposed to control (5.4 mM) or low potassium (3.7 mM, Low K+). Results from 3 independent experiments are shown. (B) Effects of low potassium on activation of extracellular signal–regulated kinase (ERK), protein kinase C (PKC), and calcium-activated cAMP response element–binding protein (CREB), determined by Western blot analysis. Representative blots from 3 independent experiments are shown. (C) Effects of pharmacological inhibitors on VSMC calcification. VSMCs were exposed to control or low-potassium media with the indicated inhibitors for 3 weeks. Calcification was determined by Alizarin red staining. (D) Effects of pharmacological inhibitors on activation of CREB. Western blot analysis of phosphorylation of CREB in C. Representative images from 3 independent experiments are shown. (E and F) Effects of CREB knockdown on low-potassium-induced VSMC calcification. VSMCs with CREB knockdown by shRNA (shCREB) or control shRNA (shScr) were exposed to control or low-potassium media for 3 weeks. Calcification was determined by Alizarin red staining. Western blot analysis was performed to determine the expression of CREB, runt-related transcription factor 2 (Runx2), and 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. (G) Effects of pharmacological inhibitors on autophagy markers. Western blot analysis of LC3 I and II levels in VSMCs exposed to control or low-potassium media for 3 weeks, in the presence or absence of indicated inhibitors. Representative results from 3 independent experiments are shown.