Possible role of parathyroid hormone-related protein as a proinflammatory cytokine in atherosclerosis
Possible role of parathyroid hormone-related protein as a proinflammatory cytokine in atherosclerosis
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DOI：
10.1161/01.str.0000078371.00577.76
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发表时间：
2003-07-01
期刊：
影响因子：
8.3
通讯作者：
Egido, JS
中科院分区：
文献类型：
--
作者：
Martín-Ventura, JL;Ortego, M;Egido, JS
背景和目的-甲状旁腺激素相关蛋白（PTHrP）是一种血管扩张肽.此外，PTHrP似乎影响血管生长，并成为风湿性和脑疾病中炎症的介质。我们检测了PTHrP在动脉粥样硬化炎症过程中的可能作用。方法-我们化学分析了26例人颈动脉粥样硬化斑块中PTHrP、1型PTH/PTHrP受体（PTH 1 R）和单核细胞趋化蛋白-1（MCP-1）的细胞定位。和MCP-1免疫染色与帽（分别为0.75 +/- 0.1对比0.29 +/- 0.04，0.5 +/- 0.1对比0.25 +/- 0.05，0.72 +/- 0.2对比0.29 +/- 0.05; P < 0.05）。PTHrP和MCP-1共定位于斑块中的常驻细胞和炎性细胞中。此外，在培养的血管平滑肌细胞（VSMC）中，PTHrP（1 - 36）增加MCP-1 mRNA（6小时时为3倍）和MCP-1蛋白（24小时时为2.5倍）。该作用被PTHrP（7-34）或各种蛋白激酶A抑制剂以及核因子-κ B（NF-κ B）抑制剂孤雌激活剂抑制。此外，PTHrP（1 - 36）引起VSMC中NF-κ B活化的增加。3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂辛伐他汀抑制PTHrP（1 - 36）诱导NF-κ B B活性和MCP-1过表达，这是逆转mevalonate.Conclusions - PTHrP似乎是一种新的促炎介质在动脉粥样硬化病变，并可能有助于颈动脉粥样硬化斑块的不稳定性。我们的数据为了解他汀类药物在动脉粥样硬化中的有益作用机制提供了新的理论基础。
Background and Purpose - Parathyroid hormone - related protein ( PTHrP) is a vasodilator peptide. In addition, PTHrP appears to affect vascular growth and to be a mediator of inflammation in rheumatic and brain disorders. We examined the possible role of PTHrP in the inflammatory process in atherosclerosisMethods - We immunohistochemically analyzed the cellular localization of PTHrP, the type 1 PTH/PTHrP receptor (PTH1R), and monocyte chemoattractant protein-1 (MCP-1) in 26 human carotid atherosclerotic plaques.Results - The inflammatory region of plaques was characterized by high PTHrP, PTH1R, and MCP-1 immunostaining in relation to the cap (0.75 +/- 0.1 versus 0.29 +/- 0.04, 0.5 +/- 0.1 versus 0.25 +/- 0.05, 0.72 +/- 0.2 versus 0.29 +/- 0.05, respectively; P < 0.05). PTHrP and MCP-1 were colocalized in both resident and inflammatory cells in the plaque. Moreover, in cultured vascular smooth muscle cells (VSMC), PTHrP( 1 - 36) increased MCP-1 mRNA (3-fold at 6 hours) and MCP-1 protein (2.5-fold at 24 hours). This effect was inhibited by either PTHrP(7-34) or various protein kinase A inhibitors and by the nuclear factor-kappa B (NF-kappa B) inhibitor parthenolide. Furthermore, PTHrP( 1 - 36) elicited an increase in NF-kappa B activation in VSMC. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin inhibited the PTHrP(1 - 36) induction of both NF-kappa B activity and MCP-1 overexpression, and this was reversed by mevalonate.Conclusions - PTHrP appears to be a novel proinflammatory mediator in the atheroma lesion and may contribute to the instability of carotid atherosclerotic plaques. Our data provide a new rationale to understand the mechanisms involved in the beneficial effects of statins in atherosclerosis.