For some time now, a deficiency in dietary potassium has been linked to progression of cardiovascular diseases, such as hypertension and atherosclerosis. A recent study by researchers from University of Alabama at Birmingham now demonstrate how this deficiency leads to the stiffening of arteries through the cellular mechanisms of vascular calcification.
Previous studies have shown that vascular calcification is a highly regulated process that involves the osteogenic differentiation of vascular smooth muscle cells (VSMCs) into bone-like cells. This change in VSMCs dictates vascular tone, and leads to disturbance of the vasculature and arterial stiffening. However, the underlying molecular mechanisms remain largely unknown.
To observe how varying levels of potassium related to calcification and stiffness, mice prone to cardiovascular disease were tested with varying levels of dietary potassium. Mice fed a low-potassium diet showed a significant increase in vascular calcification as indicated by histological staining with a calcium-binding dye. Echocardiographic analysis similarly showed an increase in mean pulse wave velocity (PWV), an indicator of aortic stiffness. Inversely, higher dietary potassium inhibited vascular calcification and stiffness. For good measure, dietary potassium levels are consistently reflected in the blood serum.
Mirroring these experiments ex vivo on a VSMC cell culture in aortic media also produced similar results. In addition, protein and mRNA expression analysis of VSMCs showed that Runx2, a key osteogenic transcription factor, was found to be upregulated by low potassium. On the other hand, SMC marker genes, α-SMA and SM22α, were found to be reduced. At the protein level, these findings suggest a direct effect of low potassium on promoting VSMC osteogenic differentiation and calcification.
At the cellular level, low-potassium was found to elevate intracellular calcium in the VSMCs, via the inward rectifier potassium channel. This was followed by the activation of key signaling proteins, protein kinase C and calcium-activated cAMP response element-binding protein (CREB). Their activation was found to ultimately increase cellular autophagy.
When autophagy was blocked, either with a chemical inhibitor or genetic knockdown, VSMC calcification was similarly diminished. This phenomenon was confirmed in mouse artery cross-sections and living-mouse models, cementing the role of autophagy in low-potassium and calcification.
Altogether, these findings establish the novel and important role for potassium in regulating vascular calcification through calcium signaling and autophagy, and by changes in smooth muscle cell gene expression. These mechanisms may offer new, much needed therapeutic strategies in our long struggle with atherosclerosis and other cardiovascular diseases.
The study was published earlier this week in JCI Insight.