MicroRNAs 29b, 133b, and 211 Regulate Vascular Smooth Muscle Calcification Mediated by High Phosphorus

Abstract

Vascular calcification is a frequent cause of morbidity and mortality in patients with CKD and the general population. The common association between vascular calcification and osteoporosis suggests a link between bone and vascular disorders. Because microRNAs (miRs) are involved in the transdifferentiation of vascular smooth muscle cells into osteoblast-like cells, we investigated whether miRs implicated in osteoblast differentiation and bone formation are involved in vascular calcification. Different levels of uremia, hyperphosphatemia, and aortic calcification were induced by feeding nephrectomized rats a normal or highphosphorus diet for 12 or 20 weeks, at which times the levels of eight miRs (miR-29b, miR-125, miR-133b, miR-135, miR-141, miR-200a, miR-204, and miR-211) in the aorta were analyzed. Compared with controls and uremic rats fed a normal diet, uremic rats fed a high-phosphorous diet had lower levels of miR-133b and miR-211 and higher levels of miR-29b that correlated respectively with greater expression of osteogenic RUNX2 and with lower expression of several inhibitors of osteoblastic differentiation. Uremia per se mildly reduced miR-133b levels only. Similar results were obtained in two in vitro models of vascular calcification (uremic serum and highcalcium and -phosphorus medium), and experiments using antagomirs and mimics to modify miR-29b, miR-133b, and miR-211 expression levels in these models confirmed that these miRs regulate the calcification process. We conclude that miR-29b, miR-133b, and miR-211 have direct roles in the vascular smooth muscle calcification induced by high phosphorus and may be new therapeutic targets in the management of vascular calcification.

Calcification of vascular smooth muscle cells is induced by secondary calciprotein particles and enhanced by tumor necrosis factor-α

“…In vitro calcification of VSMC has been widely studied using calcification medium, i.e. cell culture medium supplemented with phosphate, calcium and FBS [25,40,47,48]. Using this approach, however, calcification induction was initially variable in our hands.…”

Melatonin alleviates vascular calcification and ageing through exosomal miR‐204/miR‐211 cluster in a paracrine manner

“…Previous studies have suggested that miRNAs play a pivotal role in vascular calcification . We detected eight miRNAs related to calcification in exosomes secreted by VSMCs treated with or without MT by qRT‐PCR.…”

“…Some studies have demonstrated that miR‐204 and miR‐211 play a key role in vascular calcification . We hypothesised that exosomal miR‐204 and miR‐211 participated in the process of vascular osteogenic differentiation and senescence by a paracrine mechanism.…”

“…Vascular ageing is a degenerative change in the structure and function of the cardiovascular system. Moreover, vascular calcification, an important phenotype of vascular ageing, is a complex and adjustable biological process that is regulated by various microRNA (miRNA) networks . However, the role and mechanisms of vascular calcification and ageing remain unknown.…”

Vascular calcification: the role of microRNAs

“…Emerging evidence suggests that complex networks of multiple miRs are responsible for the development of vascular calcification, primarily by targeting the osteogenic master regulator RUNX2 (31,32) (Figure 1). Accordingly, miRs might be useful as biomarkers of early vascular calcification, allowing timely intervention to prevent progression of this process (32). In addition, miRs might represent promising targets for the prevention of vascular calcification and its adverse cardiovascular sequelae.…”