FCGR2A
Low affinity immunoglobulin gamma Fc region receptor II-a precursor (IgG Fc receptor II-a) (CDw32) (Fc-gamma RII-a) (Fc-gamma-RIIa) (FcRII-a) (CD32 antigen) [CD32] [FCG2] [FCGR2A1] [IGFR2]
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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.
MeSH Terms
- Aging
- Animals
- C-Reactive Protein
- Cell Transdifferentiation
- Cells, Cultured
- Chondrogenesis
- Disease Models, Animal
- Glucuronidase
- Humans
- Mice
- Muscle, Smooth, Vascular
- Myocytes, Smooth Muscle
- Osteogenesis
- Oxidative Stress
- RNA, Small Interfering
- Receptors, IgG
- Renal Insufficiency, Chronic
- Signal Transduction
- Vascular Calcification
Keywords
- CKD
- CRP
- osteo-/chondrogenic signaling
- oxidative stress
- vascular calcification
- vascular smooth muscle cells
The functional single nucleotide polymorphism rs1801274 in the FCGR2A gene (His131Arg) influences the efficiency of hIgG2 binding, the main isotype produced in response to encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae. In contrast to the receptor with the His131 allele, FcgammaRIIa-Arg131 binds hIgG2 poorly and carriers of this variant have been shown to be much more susceptible to succumb to bacterial pneumonia or meningitis. As bacteraemic pneumonia is one of the leading causes of death in elderly individuals, we hypothesized that the Arg131 variant could be a major mortality factor in the old. We analysed the FCGR2A-His131Arg polymorphism in a group of 408 German centenarians and two samples of younger Germans aged 60-75 and 18-49 years, respectively. No statistically significant differences were observed between the three age groups, neither at the allele nor at the genotype level. Apparently, the ability to reach old age is largely unaffected by the genetically determined efficacy of the FCGR2A-based immune response. However, the severely reduced ability of FCGR2A-131Arg carriers to eliminate encapsulated bacteria must apparently be compensated by an alternative mechanism, possibly involving other genetic survival factors.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Amino Acid Substitution
- Genetic Predisposition to Disease
- Germany
- Haemophilus Infections
- Haemophilus influenzae
- Humans
- Longevity
- Middle Aged
- Pneumonia, Bacterial
- Pneumonia, Pneumococcal
- Polymorphism, Single Nucleotide
- Receptors, IgG
- Streptococcus pneumoniae