Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure.
Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure.
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DOI：
10.1016/j.redox.2017.09.015
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Panchatcharam M
中科院分区：
文献类型：
--
作者：
Chandra M;Escalante-Alcalde D;Bhuiyan MS;Orr AW;Kevil C;Morris AJ;Nam H;Dominic P;McCarthy KJ;Miriyala S;Panchatcharam M
由Plpp 3基因编码的脂质磷酸酶3（LPP 3）是使生物活性脂质介质溶血磷脂酸（LPA）去磷酸化的酶。为了研究LPP 3在心肌中的作用，我们产生了心脏特异性Plpp 3缺陷小鼠品系。尽管这些小鼠在出生时与整体Plpp 3敲除小鼠相比是存活的，但它们显示出约8个月的死亡率增加。LPP 3缺陷小鼠具有增大的心脏，如通过超声心动图观察到的左心室性能降低。心脏特异性Plpp 3缺陷小鼠与其Plpp 3同窝出生的小鼠相比具有更长的心室有效不应期。基于细胞表面积的分析，我们观察到Lpp 3的缺乏增强了心肌细胞肥大。我们发现Lpp 3信号的缺乏是通过Rho和磷酸化ERK途径的激活介导的。胎儿基因利钠肽A和B（Nppa和NppB）表达水平升高，表明心肌功能障碍。这些小鼠还表现出线粒体功能障碍，如通过线粒体生物能量学测量的基础耗氧率、线粒体ATP产生和备用呼吸能力的显著降低（P < 0.001）所证明的。这些心脏的组织学和透射电子显微镜显示肌节组织和闰盘破坏，线粒体中嵴和空泡形成明显中断。我们的研究结果表明，LPA/LPP 3信号通路在心肌细胞的正常功能中起着重要作用。与PLPP的其他亚型相比，PLPP 3在心脏中起着突出的作用。缺乏PLPP 3会导致心脏功能恶化。PLPP 3调节心肌细胞中的LPA信号传导。PLPP 3的存在是最佳线粒体功能所必需的。增加的自由基产生用活化的PLPP 3减轻。
Lipid Phosphate phosphatase 3 (LPP3), encoded by the Plpp3 gene, is an enzyme that dephosphorylates the bioactive lipid mediator lysophosphatidic acid (LPA). To study the role of LPP3 in the myocardium, we generated a cardiac specific Plpp3 deficient mouse strain. Although these mice were viable at birth in contrast to global Plpp3 knockout mice, they showed increased mortality ~ 8 months. LPP3 deficient mice had enlarged hearts with reduced left ventricular performance as seen by echocardiography. Cardiac specific Plpp3 deficient mice had longer ventricular effective refractory periods compared to their Plpp3 littermates. We observed that lack of Lpp3 enhanced cardiomyocyte hypertrophy based on analysis of cell surface area. We found that lack of Lpp3 signaling was mediated through the activation of Rho and phospho-ERK pathways. There are increased levels of fetal genes Natriuretic Peptide A and B (Nppa and Nppb) expression indicating myocardial dysfunction. These mice also demonstrate mitochondrial dysfunction as evidenced by a significant decrease (P < 0.001) in the basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity as measured through mitochondrial bioenergetics. Histology and transmission electron microscopy of these hearts showed disrupted sarcomere organization and intercalated disc, with a prominent disruption of the cristae and vacuole formation in the mitochondria. Our findings suggest that LPA/LPP3-signaling nexus plays an important role in normal function of cardiomyocytes. PLPP3 plays a prominent role in the heart compared to other isoforms of PLPP. Lack of PLPP3 results in deteriorating cardiac function. PLPP3 regulates LPA signaling in cardiomyocytes. Presence of PLPP3 is required for optimal mitochondrial function. Increased free radical production is mitigated with activated PLPP3.
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影响因子：
4.6
作者：
Maguire, CT;Wakimoto, H;Berul, CI
通讯作者：
Berul, CI
影响因子：
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作者：
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DOI：
10.1152/ajpheart.00074.2010
发表时间：
2010-09-01
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DOI：
10.1080/00365510310003265
发表时间：
2003-01-01
影响因子：
2.1
作者：
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通讯作者：
Chen, JH
DOI：
10.1016/j.bbalip.2012.07.012
发表时间：
2013-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Ren H;Panchatcharam M;Mueller P;Escalante-Alcalde D;Morris AJ;Smyth SS
通讯作者：
Smyth SS