AUTHOR=Cai Lin , Fan Guangpu , Wang Fang , Liu Si , Li Tiewei , Cong Xiangfeng , Chun Jerold , Chen Xi 

TITLE=Protective Role for LPA3 in Cardiac Hypertrophy Induced by Myocardial Infarction but Not by Isoproterenol

JOURNAL=Frontiers in Physiology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2017.00356

DOI=10.3389/fphys.2017.00356

ISSN=1664-042X

ABSTRACT=<p><bold>Background:</bold> We previously reported that lysophosphatidic acid (LPA) promoted cardiomyocyte hypertrophy <italic>in vitro</italic> via one of its G protein-coupled receptor subtypes, LPA<sub>3</sub>. In this study, we examined the role of LPA<sub>3</sub> in cardiac hypertrophy induced by isoproterenol (ISO) and myocardial infarction.</p><p><bold>Methods:</bold><italic>In vitro</italic>, neonatal rat cardiomyocytes (NRCMs) were subjected to LPA<sub>3</sub> 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. <italic>In vivo</italic>, <inline-formula><mml:math id="M1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mrow><mml:mtext>LPA</mml:mtext></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:mo>/</mml:mo><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math></inline-formula> 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. <inline-formula><mml:math id="M2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mrow><mml:mtext>LPA</mml:mtext></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:mo>/</mml:mo><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math></inline-formula> 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.</p><p><bold>Results:</bold><italic>In vitro</italic>, we found that knocked-down LPA<sub>3</sub> in NRCMs did not attenuate ISO-induced hypertrophy, and propranolol was unable to abolish LPA-induced hypertrophy. <italic>In vivo</italic>, chronic ISO infusion caused cardiac hypertrophy in wild-type mice, while hypertrophic responses to ISO infusion were not attenuated in <inline-formula><mml:math id="M3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mrow><mml:mtext>LPA</mml:mtext></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:mo>/</mml:mo><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math></inline-formula> mice. However, in a myocardial infarction (MI) model, <inline-formula><mml:math id="M4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mrow><mml:mtext>LPA</mml:mtext></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow><mml:mrow><mml:mo>-</mml:mo><mml:mo>/</mml:mo><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math></inline-formula> 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.</p><p><bold>Conclusions:</bold> Our data show that LPA<sub>3</sub> 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 <italic>in vivo</italic> and <italic>in vitro</italic>. These results implicate LPA-LPA<sub>3</sub> 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<sub>3</sub> signaling might represent a new strategy for preventing the stressed myocardium from ischemia injury.</p>