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

Lin, Cai; Fan, Guangpu; Wang, Fang; Liu, Si; Li, Tiewei; Xu, Cong; Chun, Jerold; Chen, Xi

doi:10.3389/fphys.2017.00356

Cited by 15 publications

(10 citation statements)

References 57 publications

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“…Despite recent studies implicating LPA receptor signaling in cardiovascular disease [ 9 – 13 ] and obesity/diabetes [ 20 , 22 – 24 , 30 – 32 ], it remains unclear which of the six so far identified LPA receptors (LPA1-6) are expressed in the heart and cardiomyocytes and whether myocardial LPA receptor expression is regulated by changes in metabolic status. Therefore, we examined LPA receptor mRNA levels in the heart from mice that were fed either chow or HFHS diet for 16 weeks in the fed state and following a 16-h fast.…”

Section: Resultsmentioning

confidence: 99%

“…Prior studies also showed that LPA levels increase with myocardial infarction [ 16 , 17 ]. On the other hand, a recent study suggested that LPA1 and LPA3 signaling provide a protective effect against ischemia-reperfusion injury in rats and sequelae from myocardial infarction in mice [ 11 , 13 ]. Bouchareb et al [ 12 ] identified the autotaxin-LPA signaling axis as a major contributor to aortic valve stenosis as it promotes aortic valve inflammation and mineralization.…”

Section: Introductionmentioning

confidence: 99%

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Lysophosphatidic acid receptor mRNA levels in heart and white adipose tissue are associated with obesity in mice and humans

et al. 2017

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BackgroundLysophosphatidic acid (LPA) receptor signaling has been implicated in cardiovascular and obesity-related metabolic disease. However, the distribution and regulation of LPA receptors in the myocardium and adipose tissue remain unclear.ObjectivesThis study aimed to characterize the mRNA expression of LPA receptors (LPA1-6) in the murine and human myocardium and adipose tissue, and its regulation in response to obesity.MethodsLPA receptor mRNA levels were determined by qPCR in i) heart ventricles, isolated cardiomyocytes, and perigonadal adipose tissue from chow or high fat-high sucrose (HFHS)-fed male C57BL/6 mice, ii) 3T3-L1 adipocytes and HL-1 cardiomyocytes under conditions mimicking gluco/lipotoxicity, and iii) human atrial and subcutaneous adipose tissue from non-obese, pre-obese, and obese cardiac surgery patients.ResultsLPA1-6 were expressed in myocardium and white adipose tissue from mice and humans, except for LPA3, which was undetectable in murine adipocytes and human adipose tissue. Obesity was associated with increased LPA4, LPA5 and/or LPA6 levels in mice ventricles and cardiomyocytes, HL-1 cells exposed to high palmitate, and human atrial tissue. LPA4 and LPA5 mRNA levels in human atrial tissue correlated with measures of obesity. LPA5 mRNA levels were increased in HFHS-fed mice and insulin resistant adipocytes, yet were reduced in adipose tissue from obese patients. LPA4, LPA5, and LPA6 mRNA levels in human adipose tissue were negatively associated with measures of obesity and cardiac surgery outcomes. This study suggests that obesity leads to marked changes in LPA receptor expression in the murine and human heart and white adipose tissue that may alter LPA receptor signaling during obesity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic acid receptor mRNA levels in heart and white adipose tissue are associated with obesity in mice and humans

et al. 2017

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“…These data indirectly support the findings in the current study. In addition, LPA3 knockout mice exhibited reduced cardiac hypertrophy compared to wild-type mice post-MI ( Cai et al, 2017 ), indicating that LPA/LPA3 signaling is required for cardiac hypertrophy after MI. In terms of regulation of cardiac hypertrophy, this report supports the mention in the present study.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Is Associated With Cardiac Dysfunction and Hypertrophy by Suppressing Autophagy via the LPA3/AKT/mTOR Pathway

Yang

Han

et al. 2018

Front. Physiol.

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Background: Lysophosphatidic acid (LPA), as a phospholipid signal molecule, participates in the regulation of various biological functions. Our previous study demonstrated that LPA induces cardiomyocyte hypertrophy in vitro; however, the functional role of LPA in the post-infarct heart remains unknown. Growing evidence has demonstrated that autophagy is involved in regulation of cardiac hypertrophy. The aim of the current work was to investigate the effects of LPA on cardiac function and hypertrophy during myocardial infarction (MI) and determine the regulatory role of autophagy in LPA-induced cardiomyocyte hypertrophy.Methods: In vivo experiments were conducted in Sprague-Dawley rats subjected to MI surgery or a sham operation, and rats with MI were assigned to receive an intraperitoneal injection of LPA (1 mg/kg) or vehicle for 5 weeks. The in vitro experiments were conducted in H9C2 cardiomyoblasts.Results: LPA treatment aggravated cardiac dysfunction, increased cardiac hypertrophy, and reduced autophagy after MI in vivo. LPA suppressed autophagy activation, as indicated by a decreased LC3II-to-LC3I ratio, increased p62 expression, and reduced autophagosome formation in vitro. Rapamycin, an autophagy enhancer, attenuated LPA-induced autophagy inhibition and H9C2 cardiomyoblast hypertrophy, while autophagy inhibition with Beclin1 siRNA did not further enhance the hypertrophic response in LPA-treated cardiomyocytes. Moreover, we demonstrated that LPA suppressed autophagy through the AKT/mTOR signaling pathway because mTOR and PI3K inhibitors significantly prevented LPA-induced mTOR phosphorylation and autophagy inhibition. In addition, we found that knockdown of LPA3 alleviated LPA-mediated autophagy suppression in H9C2 cardiomyoblasts, suggesting that LPA suppresses autophagy through activation of the LPA3 and AKT/mTOR pathways.Conclusion: These findings suggest that LPA plays an important role in mediating cardiac dysfunction and hypertrophy after a MI, and that LPA suppresses autophagy through activation of the LPA3 and AKT/mTOR pathways to induce cardiomyocyte hypertrophy.

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“…Next, we tested whether the up-regulation of CPA4 in hypertrophic hearts was conserved across species. Cardiac hypertrophy was induced in C57BL/6 mice by subcutaneous treatment of ISO (50 mg/kg/day) for continuous 28 days using a protocol reported previously [22]. ISO treatment induced the decrease in fraction shortening and ejection fraction in mice ( Figure 1D,E).…”

Section: The Expression Of Cpa4 Is Up-regulated In Human and Mouse Hymentioning

confidence: 68%

“…Mice were anesthetized with isoflurane and body temperature maintained on a circulating heated waterpad. The cardiac hypertrophy in mouse was induced by subcutaneously chronic infusion of ISO (Sigma; 50 mg/kg/day) with ALZet minipump 2004 for 28 days, as described in previous work [22]. The animal experiments were performed in the Animal Center of Hebei Medical University.…”

Section: Animal Studymentioning

confidence: 99%

Carboxypeptidase A4 promotes cardiomyocyte hypertrophy through activating PI3K-AKT-mTOR signaling

et al. 2020

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Carboxypeptidase A4 (CPA4) is a member of the metallocarboxypeptidase family. Current studies have identified the roles of CPA4 in cancer biology and insulin sensitivity. However, the roles of CPA4 in other diseases are not known. In the present study, we investigated the roles of CPA4 in cardiac hypertrophy. The expression of CPA4 was significantly increased in the hypertrophic heart tissues of human patients and isoproterenol (ISO)-induced hypertrophic heart tissues of mice. We next knocked down Cpa4 with shRNA or overexpressed Cpa4 using adenovirus in neonatal rat cardiomyocytes and induced cardiomyocyte hypertrophy with ISO. We observed that Cpa4 overexpression promoted whereas Cpa4 knockdown reduced ISO-induced growth of cardiomyocyte size and overexpression of hypertrophy marker genes, such as myosin heavy chain β (β-Mhc), atrial natriuretic peptide (Anp), and brain natriuretic peptide (Bnp). Our further mechanism study revealed that the mammalian target of rapamycin (mTOR) signaling was activated by Cpa4 in cardiomyocytes, which depended on the phosphoinositide 3-kinase (PI3K)-AKT signaling. Besides, we showed that the PI3K-AKT-mTOR signaling was critically involved in the roles of Cpa4 during cardiomyocyte hypertrophy. Collectively, these results demonstrated that CPA4 is a regulator of cardiac hypertrophy by activating the PI3K-AKT-mTOR signaling, and CPA4 may serve as a promising target for the treatment of hypertrophic cardiac diseases.

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

Cited by 15 publications

References 57 publications

Lysophosphatidic acid receptor mRNA levels in heart and white adipose tissue are associated with obesity in mice and humans

Lysophosphatidic acid receptor mRNA levels in heart and white adipose tissue are associated with obesity in mice and humans

Lysophosphatidic Acid Is Associated With Cardiac Dysfunction and Hypertrophy by Suppressing Autophagy via the LPA3/AKT/mTOR Pathway

Carboxypeptidase A4 promotes cardiomyocyte hypertrophy through activating PI3K-AKT-mTOR signaling

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