FDPS
Farnesyl pyrophosphate synthase (EC 2.5.1.10) (FPP synthase) (FPS) ((2E,6E)-farnesyl diphosphate synthase) (Dimethylallyltranstransferase) (EC 2.5.1.1) (Farnesyl diphosphate synthase) (Geranyltranstransferase) [FPS] [KIAA1293]
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Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many normal aging characteristics. This disorder is caused by mutation in the LMNA gene leading to the production of progerin which induces misshapen nuclei, cellular senescence, and aging. We previously showed that the phospholipase A2 receptor (PLA2R1) promotes senescence induced by replicative, oxidative, and oncogenic stress but its role during progerin-induced senescence and in progeria is currently unknown. Here, we show that knockdown of PLA2R1 prevented senescence induced by progerin expression in human fibroblasts and markedly delayed senescence of HGPS patient-derived fibroblasts. Whole-body knockout of Pla2r1 in a mouse model of progeria decreased some premature aging phenotypes, such as rib fracture and decreased bone content, together with decreased senescence marker. Progerin-expressing human fibroblasts exhibited a high frequency of misshapen nuclei and increased farnesyl diphosphate synthase (FDPS) expression compared to controls; knockdown of PLA2R1 reduced the frequency of misshapen nuclei and normalized FDPS expression. Pamidronate, a FDPS inhibitor, also reduced senescence and misshapen nuclei. Downstream of PLA2R1, we found that p53 mediated the progerin-induced increase in FDPS expression and in misshapen nuclei. These results suggest that PLA2R1 mediates key premature aging phenotypes through a p53/FDPS pathway and might be a new therapeutic target.
MeSH Terms
- Aging, Premature
- Animals
- Cell Line
- Cell Nucleus
- Cell Nucleus Shape
- Cellular Senescence
- Disease Models, Animal
- Geranyltranstransferase
- Humans
- Lamin Type A
- Mice, Inbred C57BL
- Phenotype
- Progeria
- Receptors, Phospholipase A2
- Tumor Suppressor Protein p53
Keywords
- cellular senescence
- p53
- progeroid diseases
- signaling
The mevalonate pathway is an important metabolic pathway that plays a key role in multiple cellular processes. The aim of this study was to define whether the enzyme expression in mevalonate pathway changes during cardiovascular remodelling in spontaneously hypertensive rats (SHR). Hearts and thoracic aortas were removed for the study of cardiovascular remodeling in SHR and Wistar-Kyoto rats (WKY). The protein expression of the enzymes in hearts, aortas and livers was analyzed by western blot. The histological measurements showed that the mass and the size of cardiomyocytes, the media thickness and the media cross-sectional area (MCSA) of the thoracic aorta were all increased in SHR since 3 weeks of age. In the heart, there was overexpression of some enzymes, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), farnesyl diphosphate synthase (FDPS), and geranylgeranyltransferase type I (GGTase-I), and downregulation of squalene synthetase (SQS) in SHR since 3 weeks of age. In the aorta, besides similar expressions of HMGR, SQS, FDPS and GGTase-I as in the heart, there was upregulation of farnesyltransferase α at 16 and 25 weeks of age and of farnesyltransferase β in 25-weeks-old SHR. Western blot demonstrated overexpression of HMGR and downregulation of SQS in SHR livers at all ages tested. The cardiovascular remodeling of SHR preceded the development of hypertension, and altered expression of several key enzymes in the mevalonate pathway may play a potential pathophysiological role in cardiovascular remodeling.
MeSH Terms
- Age Factors
- Aging
- Alkyl and Aryl Transferases
- Analysis of Variance
- Animals
- Aorta, Thoracic
- Blood Pressure
- Blotting, Western
- Cholesterol, HDL
- Cholesterol, LDL
- Disease Models, Animal
- Farnesyl-Diphosphate Farnesyltransferase
- Farnesyltranstransferase
- Geranyltranstransferase
- Hydroxymethylglutaryl CoA Reductases
- Hypertension
- Liver
- Male
- Mevalonic Acid
- Myocardium
- Rats
- Rats, Inbred SHR
- Rats, Inbred WKY
- Ventricular Remodeling