Abstract
Medial vascular calcification, a major pathophysiological process associated with cardiovascular disease and mortality, involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). In chronic kidney disease (CKD), osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification is mainly driven by hyperphosphatemia, resulting from impaired elimination of phosphate by the diseased kidneys. Hyperphosphatemia with subsequent vascular calcification is a hallmark of klotho-hypomorphic mice, which are characterized by rapid development of multiple age-related disorders and early death. In those animals, hyperphosphatemia results from unrestrained formation of 1,25(OH)2D3 with subsequent retention of calcium and phosphate. Analysis of klotho-hypomorphic mice and mice with vitamin D3 overload uncovered several pathophysiological mechanisms participating in the orchestration of vascular calcification and several therapeutic opportunities to delay or even halt vascular calcification. The present brief review addresses the beneficial effects of bicarbonate, carbonic anhydrase inhibition, magnesium supplementation, mineralocorticoid receptor (MR) blockage, and ammonium salts. The case is made that bicarbonate is mainly effective by decreasing intestinal phosphate absorption, and that carbonic anhydrase inhibition leads to metabolic acidosis, which counteracts calcium-phosphate precipitation and VSMC transdifferentiation. Magnesium supplementation, MR blockage and ammonium salts are mainly effective by interference with osteo-/chondrogenic signaling in VSMCs. It should be pointed out that the, by far, most efficient substances are ammonium salts, which may virtually prevent vascular calcification. Future research will probably uncover further therapeutic options and, most importantly, reveal whether these observations in mice can be translated into treatment of patients suffering from vascular calcification, such as patients with CKD.
Highlights
Medial vascular calcification is a key pathophysiological process associated with the risk of cardiovascular events in a variety of clinical conditions such as aging, diabetes, and chronic kidney disease (CKD) [1, 2]
Acidic medium prevented the phosphate-induced upregulation of ALPL mRNA expression in primary human aortic smooth muscle cells, indicating that extracellular acidosis interferes with osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs) [64]
Further in vitro experiments revealed that inhibition of the vacuolar H+ ATPase with bafilomycin A1 or following dissipation of the pH gradient across the membranes of acidic cellular compartments with methylamine disrupted phosphate-induced TGFβ1-dependent osteo-/chondrogenic signaling in VSMCs [131], supporting the hypothesis that vascular acidic cellular compartments are necessary for promoting vascular calcification
Summary
Medial vascular calcification is a key pathophysiological process associated with the risk of cardiovascular events in a variety of clinical conditions such as aging, diabetes, and chronic kidney disease (CKD) [1, 2]. Acetazolamide treatment of klotho-hypomorphic mice blunted the calcifications in trachea, lung, kidney, stomach, intestine, and vascular tissues, reversed the excessive aortic Alpl transcript levels as a marker of aortic osteo-/chondrogenic signaling, increased the plasma concentrations of the calcification counteracting proteins osteoprotegerin, osteopontin as well as fetuin-A [68,69,70] and, tripled the life span despite unaltered plasma concentrations of FGF23, 1,25(OH)2D3, calcium and phosphate [64]. Acidic medium prevented the phosphate-induced upregulation of ALPL mRNA expression in primary human aortic smooth muscle cells, indicating that extracellular acidosis interferes with osteo-/chondrogenic transdifferentiation of VSMCs [64].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
