Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation

Abstract

Vascular calcification (VC) is a major risk factor for cardiovascular mortality in chronic renal failure (CRF) patients, but the pathogenesis remains partially unknown and effective therapeutic targets should be urgently explored. Here we pursued the therapeutic role of rapamycin in CRF-related VC. Mammalian target of rapamycin (mTOR) signal was activated in the aortic wall of CRF rats. As expected, oral rapamycin administration significantly reduced VC by inhibiting mTOR in rats with CRF. Further in vitro results showed that activation of mTOR by both pharmacological agent and genetic method promoted, while inhibition of mTOR reduced, inorganic phosphate-induced vascular smooth muscle cell (VSMC) calcification and chondrogenic/osteogenic gene expression, which were independent of autophagy and apoptosis. Interestingly, the expression of Klotho, an antiaging gene that suppresses VC, was reduced in calcified vasculature, whereas rapamycin reversed membrane and secreted Klotho decline through mTOR inhibition. When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1, Klotho mRNA was further decreased in phosphate-treated VSMCs, suggesting a vital association between mTOR signaling and Klotho expression. More importantly, rapamycin failed to reduce VC in the absence of Klotho by using either siRNA knockdown of Klotho or Klotho knockout mice. Thus, Klotho has a critical role in mediating the observed decrease in calcification by rapamycin in vitro and in vivo.

Autophagy: A double-edged sword in intervertebral disk degeneration

“…Activation of autophagy has been shown to ameliorate calcification in vascular smooth muscle cells [115][116][117]. Xu and colleagues have demonstrated that intermittent cyclic mechanical tension (ICMT) induces the calcification of rat CEP chondrocytes through downregulation of transforming growth factor-β1 (TGF-β1) expression in vitro [118].…”

Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients

“…It has been reported that immunosuppressive protocols might modulate Klotho expression [7,10,11]. Zhao et al [7] showed activation of mTOR signaling in a rat model of chronic renal failure.…”

“…Zhao et al [7] showed activation of mTOR signaling in a rat model of chronic renal failure. They revealed that mTOR activation can suppress Klotho expression in vitro and in vivo, resulting in vascular calcification.…”

“…A recent study demonstrated that inhibition of the mammalian target of rapamycin (mTOR) upregulates Klotho expression [7]. To evaluate serial changes in Klotho levels with renal transplantation, we measured sKlotho levels in ESRD patients before and after transplantation.…”

Microsomal Prostaglandin E Synthase-1–Derived PGE 2 Inhibits Vascular Smooth Muscle Cell Calcification

“…Compared with wild-type (WT) mice, the aortic rings of COX-2 −/− mice showed a significant increase of calcium deposition and von Kossa staining with high-Pi stimulation ( Figure 1F and 1G). In addition, considering the prevalence of vascular medial calcification in patients with CRF, 7 we adopted a modified adenine diet-induced CRF mice model 18,19 ( Figure 1H) for exploring the role of COX-2 in vascular calcification in vivo. On the basis of Table I in the online-only Data Supplement, the body weight of WT and COX-2 −/− mice fed with adenine diet was significantly decreased compared with chow diet mice, respectively.…”