Cai Lin, Fan Guangpu, Wang Fang, Liu Si, Li Tiewei, Cong Xiangfeng, Chun Jerold, Chen Xi
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China.
Cardiovascular Surgery Department, FuWai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China.
Front Physiol. 2017 May 30;8:356. doi: 10.3389/fphys.2017.00356. eCollection 2017.
We previously reported that lysophosphatidic acid (LPA) promoted cardiomyocyte hypertrophy via one of its G protein-coupled receptor subtypes, LPA. In this study, we examined the role of LPA in cardiac hypertrophy induced by isoproterenol (ISO) and myocardial infarction. , neonatal rat cardiomyocytes (NRCMs) were subjected to LPA knocked-down, or pretreated with a β-adrenergic receptor (β-AR) antagonist (propranolol) before LPA/ISO treatment. Cardiomyocyte size and hypertrophic gene (ANP, BNP) mRNA levels were determined. , [Formula: see text] and wild-type mice were implanted subcutaneously with an osmotic mini-pump containing ISO or vehicle for 2 weeks; echocardiography was performed to determine the heart weight/body weight ratio, cardiomyocyte cross-sectional area, and level of ANP mRNA expression. [Formula: see text] and wild-type mice were subjected to permanent coronary artery ligation or sham surgery for 4 weeks; cardiac function, including the degree of hypertrophy and infarction size, was determined. , we found that knocked-down LPA in NRCMs did not attenuate ISO-induced hypertrophy, and propranolol was unable to abolish LPA-induced hypertrophy. , chronic ISO infusion caused cardiac hypertrophy in wild-type mice, while hypertrophic responses to ISO infusion were not attenuated in [Formula: see text] mice. However, in a myocardial infarction (MI) model, [Formula: see text] mice exhibited reduced cardiac hypertrophy compared to wild-type mice at 4 weeks post-MI, which was associated with reduced cardiac function and increased infarct size. Our data show that LPA appears to play a protective role in myocardial hypertrophy post-MI, but does not appear to be involved in the hypertrophy that occurs in response to β-AR stimulation and . These results implicate LPA-LPA lipid signaling in cardiac hypertrophy occurring after pathological insults like MI, which presents a new variable in β-AR-independent hypertrophy. Thus, modulation of LPA signaling might represent a new strategy for preventing the stressed myocardium from ischemia injury.
我们之前报道过，溶血磷脂酸（LPA）通过其G蛋白偶联受体亚型之一LPA促进心肌细胞肥大。在本研究中，我们研究了LPA在异丙肾上腺素（ISO）诱导的心脏肥大和心肌梗死中的作用。首先，对新生大鼠心肌细胞（NRCMs）进行LPA敲低，或在LPA/ISO处理前用β-肾上腺素能受体（β-AR）拮抗剂（普萘洛尔）预处理。测定心肌细胞大小和肥大基因（ANP、BNP）mRNA水平。其次，将[公式：见正文]和野生型小鼠皮下植入含ISO或载体的渗透微型泵2周；进行超声心动图检查以确定心脏重量/体重比、心肌细胞横截面积和ANP mRNA表达水平。再次，将[公式：见正文]和野生型小鼠进行永久性冠状动脉结扎或假手术4周；测定心脏功能，包括肥大程度和梗死面积。我们发现，NRCMs中LPA敲低并未减轻ISO诱导的肥大，普萘洛尔也无法消除LPA诱导的肥大。此外，慢性ISO输注导致野生型小鼠心脏肥大，而[公式：见正文]小鼠对ISO输注的肥大反应并未减弱。然而，在心肌梗死（MI）模型中，与野生型小鼠相比，[公式：见正文]小鼠在MI后4周时心脏肥大减轻，这与心脏功能降低和梗死面积增加有关。我们的数据表明，LPA似乎在MI后心肌肥大中起保护作用，但似乎不参与因β-AR刺激而发生的肥大。这些结果表明LPA-LPA脂质信号传导参与了MI等病理损伤后发生的心脏肥大，这在不依赖β-AR的肥大中呈现出一个新变量。因此，调节LPA信号传导可能代表一种预防应激心肌缺血损伤的新策略。
