The potential role of MLC phosphatase and MAPK signalling in the pathogenesis of vascular dysfunction in heart failure.
The potential role of MLC phosphatase and MAPK signalling in the pathogenesis of vascular dysfunction in heart failure.
复制标题
DOI：
10.1111/j.1582-4934.2008.00536.x
复制
发表时间：
2008-12
影响因子：
5.3
通讯作者：
Brozovich FV
中科院分区：
文献类型：
--
作者：
Ogut O;Brozovich FV
心力衰竭的临床综合征与静息血管收缩和对一氧化氮介导的血管舒张的敏感性降低相关，本综述将重点关注肌球蛋白轻链（MLC）磷酸酶在心力衰竭血管异常发病机制中的作用。一氧化氮通过激活鸟苷酸环化酶和增加 cGMP 的产生来介导血管舒张，从而导致 I 型 cGMP 依赖性蛋白激酶 (PKGI) 的激活。然后 PKGI 激活许多产生平滑肌松弛的靶标，包括 MLC 磷酸酶。 MLC 磷酸酶是一种由三个亚基组成的全酶；功能未知的 20 kD 亚基、~38 kD 催化亚基和肌球蛋白靶向亚基 (MYPT1)。 31 bp 3' 外显子的选择性剪接生成 MYPT1 同工型，其不同之处在于 COOH 末端亮氨酸拉链 (LZ)。此外，PKGI 介导的 MLC 磷酸酶激活需要 LZ+ MYPT1 的表达。充血性心力衰竭与 LZ+ MYPT1 表达减少相关，从而导致对 cGMP 介导的平滑肌松弛的敏感性降低。除了减少后负荷的能力之外，血管紧张素转换酶 (ACE) 抑制剂还具有许多有益作用，包括维持 LZ+ MYPT1 同工型的表达，从而保持对 cGMP 介导的血管舒张的正常敏感性，以及差异调节与丝裂原激活蛋白激酶 (MAPK) 信号相关的基因。 ACE 抑制可减少循环血管紧张素 II，从而限制 MAPK 信号通路的下游激活，可能阻止血管表型的改变以保持正常的血管功能。
The clinical syndrome of heart failure is associated with both a resting vasoconstriction and reduced sensitivity to nitric oxide mediated vasodilatation, and this review will focus on the role of myosin light chain (MLC) phosphatase in the pathogenesis of the vascular abnormalities of heart failure. Nitric oxide mediates vasodilatation by an activation of guanylate cyclase and an increase in the production of cGMP, which leads to the activation of the type I cGMP-dependent protein kinase (PKGI). PKGI then activates a number of targets that produce smooth muscle relaxation including MLC phosphatase. MLC phosphatase is a holoenzyme consisting of three subunits; a 20 kD subunit of unknown function, an ∼38-kD catalytic subunit and a myosin targeting subunit (MYPT1). Alternative splicing of a 31 bp 3' exon generates MYPT1 isoforms, which differ by a COOH-terminus leucine zipper (LZ). Further, PKGI-mediated activation of MLC phosphatase requires the expression of a LZ+ MYPT1. Congestive heart failure is associated with a decrease in LZ+ MYPT1 expression, which results in a decrease in the sensitivity to cGMP-mediated smooth muscle relaxation. Beyond their ability to reduce afterload, angiotensin converting enzyme (ACE) inhibitors have a number of beneficial effects that include maintaining the expression of the LZ+ MYPT1 isoform, thereby conserving normal sensitivity to cGMP-mediated vasodilatation, as well as differentially regulating genes associated with mitogen activated protein kinase (MAPK) signalling. ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways, possibly preventing the alteration of the vascular phenotype to preserve normal vascular function.
登录
查看更多内容
影响因子：
3.3
作者：
Delp, MD;Duan, CP;Musch, TI
通讯作者：
Musch, TI
影响因子：
4.8
作者：
Fukao, M;Mason, HS;Keef, KD
通讯作者：
Keef, KD
影响因子：
20.1
作者：
GRIENDLING, KK;MINIERI, CA;ALEXANDER, RW
通讯作者：
ALEXANDER, RW
影响因子：
4.8
作者：
Deng, JT;Van Lierop, JE;Walsh, MP
通讯作者：
Walsh, MP
影响因子：
5.5
作者：
DEFEO, TT;MORGAN, KG
通讯作者：
MORGAN, KG