Low dietary potassium leads to calcified arteries and aortic stiffness,
while increased dietary potassium alleviates that in a mouse model, suggesting
dietary potassium may protect against heart disease and death from heart
disease in humans

Date:

October 5, 2017

Source:

University of Alabama at Birmingham

Summary:

Researchers
have shown, for the first time, that reduced dietary potassium promotes
elevated aortic stiffness in a mouse model. Such arterial stiffness in humans
is predictive of heart disease and death from heart disease, and it represents
an important health problem for the nation. The researchers also found that
increased dietary potassium levels lessened vascular calcification and aortic
stiffness. Furthermore, they unraveled the molecular mechanism underlying the
effects of low or high dietary potassium.

Bananas and avocados —
foods that are rich in potassium — may help protect against pathogenic
vascular calcification, also known as hardening of the arteries.

University of Alabama at
Birmingham researchers have shown, for the first time, that reduced dietary
potassium promotes elevated aortic stiffness in a mouse model, as compared with
normal-potassium-fed mice. Such arterial stiffness in humans is predictive of
heart disease and death from heart disease, and it represents an important
health problem for the nation as a whole.

The UAB researchers also
found that increased dietary potassium levels lessened vascular calcification
and aortic stiffness. Furthermore, they unraveled the molecular mechanism
underlying the effects of low or high dietary potassium.

Such knowledge of how
vascular smooth muscle cells in the arteries regulate vascular calcification
emphasizes the need to consider dietary intake of potassium in the prevention
of vascular complications of atherosclerosis. It also provides new targets for
potential therapies to prevent or treat atherosclerotic vascular calcification
and arterial stiffness.

A UAB team led by Yabing
Chen, Ph.D., UAB professor of pathology and a Research Career Scientist at the
Birmingham VA Medical Center, explored this mechanism of vascular disease three
ways: living mice fed diets that varied in potassium, mouse artery
cross-sections studied in culture medium with varying concentrations of
potassium, and mouse vascular smooth muscle cells grown in culture medium.

Working from living mice
down to molecular events in cells in culture, the UAB researchers determined a
causative link between reduced dietary potassium and vascular calcification in
atherosclerosis, as well as uncovered the underlying pathogenic mechanisms.

The animal work was
carried out in the atherosclerosis-prone mouse model, the apoliprotein
E-deficient mice, a standard model that are prone to cardiovascular disease
when fed a high-fat diet. Using low, normal or high levels of dietary potassium
— 0.3 percent, 0.7 percent and 2.1 percent weight/weight, respectively, the
UAB team found that the mice fed a low-potassium diet had a significant
increase in vascular calcification. In contrast, the mice fed a high-potassium
diet had markedly inhibited vascular calcification. Also, the low-potassium
mice had increased stiffness of their aortas, and high-potassium mice had
decreased stiffness, as indicated by the arterial stiffness indicator called
pulse wave velocity, which is measured by echocardiography in live animals.

The different levels of
dietary potassium were mirrored by different blood levels of potassium in the
three groups of mice.

When researchers looked
at arterial cross-sections in cultures that were exposed to three different
concentrations of potassium, based on normal physiological levels of potassium
in the blood, they found a direct effect for the potassium on arterial
calcification within arterial rings. Arterial rings in low-potassium had
markedly enhanced calcification, while high-potassium inhibited aortic
calcification.

“The findings have
important translational potential,” said Paul Sanders, M.D., professor of
nephrology in the UAB Department of Medicine and a co-author, “since they
demonstrate the benefit of adequate potassium supplementation on prevention of
vascular calcification in atherosclerosis-prone mice, and the adverse effect of
low potassium intake.”

Mechanistic details

In cell culture, low
potassium levels in the culture media markedly enhanced calcification of
vascular smooth muscle cells. Previous research by several labs including
Chen’s group has shown that calcification of vascular smooth muscle cells
resembles the differentiation of bone cells, which leads to the transformation
of smooth muscle cells into bone-like cells.

So the UAB researchers
tested the effect of growing vascular smooth muscle cells in low-potassium cell
culture. They found that the low-potassium conditions promoted the expression
of several gene markers that are hallmarks of bone cells, but decreased the
expression of vascular smooth muscle cell markers, suggesting the
transformation of the vascular smooth muscle cells into bone-like cells under
low-potassium conditions.

Mechanistically, they
found that low-potassium elevated intracellular calcium in the vascular smooth
muscle cells, via a potassium transport channel called the inward rectifier
potassium channel. This was accompanied by activation of several known
downstream mediators, including protein kinase C and the calcium-activated cAMP
response element-binding protein, or CREB.

In turn, CREB activation
increased autophagy — the intracellular degradation system — in the
low-potassium cells. Using autophagy inhibitors, the researchers showed that
blocking autophagy blocked calcification. Thus, autophagy plays an important
role in mediating calcification of vascular smooth muscle cells induced by the
low-potassium condition.

The roles of the CREB
activation and autophagy signals were then tested in the mouse artery
cross-section and living-mouse models, with low, normal or high levels of
potassium in the media or diet. Results in both of those systems supported the
vital role for potassium to regulate vascular calcification through calcium
signaling, CREB and autophagy.

Besides Chen and Sanders,
co-authors of the paper, “Dietary potassium regulates vascular
calcification and arterial stiffness,” published in JCI Insight, are Yong
Sun, Chang Hyun Byon and Youfeng Yang, UAB Department of Pathology; Wayne E.
Bradley, Louis J. Dell’Italia and Anupam Agarwal, UAB Department of Medicine;
and Hui Wu, UAB Department of Pediatric Dentistry. Sanders, Agarwal and Chen
are also members of the Research Department, Veterans Affairs Birmingham
Medical Center.

Materials provided by University of Alabama at Birmingham. Note: Content may
be edited for style and length.

Journal Reference:

1.    Yong Sun, Chang Hyun
Byon, Youfeng Yang, Wayne E. Bradley, Louis J. Dell’Italia, Paul W. Sanders,
Anupam Agarwal, Hui Wu, Yabing Chen. Dietary potassium regulates vascular
calcification and arterial stiffness. JCI Insight, 2017; 2 (19) DOI:
10.1172/jci.insight.94920