Abstract
Medial vascular calcification occurs during the aging process and is strongly accelerated by chronic kidney disease (CKD). Elevated C-reactive protein (CRP) levels are associated with vascular calcification, cardiovascular events and mortality in CKD patients. CRP is an important promoter of vascular inflammation. Inflammatory processes are critically involved in initiation and progression of vascular calcification. Thus, the present study explored a possible impact of CRP on vascular calcification. We found that CRP promoted osteo-/chondrogenic transdifferentiation and aggravated phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of primary human aortic smooth muscle cells (HAoSMCs). These effects were paralleled by increased cellular oxidative stress and corresponding pro-calcific downstream-signaling. Antioxidants or p38 MAPK inhibition suppressed CRP-induced osteo-/chondrogenic signaling and mineralization. Furthermore, silencing of Fc fragment of IgG receptor IIa (FCGR2A) blunted the pro-calcific effects of CRP. Vascular CRP expression was increased in the klotho-hypomorphic mouse model of aging as well as in HAoSMCs during calcifying conditions. In conclusion, CRP augments osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells through mechanisms involving FCGR2A-dependent induction of oxidative stress. Thus, systemic inflammation may actively contribute to the progression of vascular calcification.
Highlights
Medial vascular calcification is characterized by the deposition of calcium phosphate in the media of arteries [1]
To determine whether C-reactive protein (CRP) may contribute to vascular calcification, possible direct effects of CRP on osteo/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs) were investigated
CRP increased the expression and activity of the osteogenic enzyme tissue-nonspecific alkaline phosphatase (ALPL) (Figure 1C, D). These effects were paralleled by reduced protein levels of the smooth muscle-specific marker α-smooth muscle actin in CRP-treated human aortic smooth muscle cells (HAoSMCs) as compared to control-treated HAoSMCs (Figure 1E)
Summary
Medial vascular calcification is characterized by the deposition of calcium phosphate in the media of arteries [1]. This process occurs during aging, but is strongly accelerated by chronic kidney disease (CKD), a condition of accelerated vascular aging [2, 3]. Osteo-/chondrogenic transdifferentiation of VSMCs and subsequent vascular calcification are tightly controlled by intracellular signaling pathways [5, 8, 9, 11]. Various pathological factors activate pro-inflammatory signaling pathways to promote or augment VSMCs osteoinduction and calcification [12,13,14,15]
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