Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation

Author(s):  
Yejiao Shen ◽  
Xia Wang ◽  
Ruosen Yuan ◽  
Xin Pan ◽  
Xiaoxiao Yang ◽  
...  
2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
L Shen ◽  
Y Shen ◽  
X Wang ◽  
B He

Abstract Aims Pathological cardiac hypertrophy induced by activation of the renin–angiotensin–aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect. Methods and results Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E prostanoid (EP)3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1. Conclusion In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1–MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy. FUNDunding Acknowledgement Type of funding sources: None.


2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Xinhua Yan ◽  
Jillian Onufrak ◽  
Yongyao Yang ◽  
Juyong Lee ◽  
John Fuseler ◽  
...  

We previously reported that a dual PI3K-mTOR inhibitor BEZ235 (BEZ) induced cardiac hypertrophy. Here, we investigated potential mechanisms. Methods: three month old FVB/n female mice were treated with BEZ for five weeks. Cardiac function was monitored by serial echocardiography during the treatment and hemodynamic measurements at the end of the study. Cell signaling was analyzed by RT-PCR, Western blotting and ELISA. Results: BEZ induced a dose-dependent increase of left ventricular (LV) wall thickness and systolic function. These were associated with increased hypertrophic markers ANP, BNP, β-MHC and α-skeletal actin in the heart. In addition, in chronic BEZ-treated mouse hearts, the activations of PI3Ks, mTOR and ERK were increased. We conducted further studies to understand these contradictory results. We found that BEZ induced an increase of hepatic gluconeogenesis gene expression which was associated with increased fasting glucose, increased serum insulin level, a worsened glucose and pyruvate tolerance and increased IGFR/Insulin receptor activation in the heart. Injections of insulin lowered blood glucose, improved glucose and pyruvate tolerance, but further aggravated BEZ-induced cardiac dysfunction. On the other hand, OSI-906 (an IGFR/IR inhibitor) normalized cardiac function in BEZ-treated mice. Conclusions: Chronic BEZ treatment induced cardiac hypertrophy may be caused by increased insulin receptor activation in the heart.


Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ajeeth K Pingili ◽  
Chi Yong Song ◽  
Ji Soo Shin ◽  
Joseph V Bonventre ◽  
Kafait U Malik

Previously we reported that angiotensin (Ang) II-induced hypertension and associated cardiovascular and renal dysfunction are mediated by cytosolic phospholipase A 2 α (cPLA 2 α) activation, the release of arachidonic acid (AA), and production of eicosanoids predominantly with pro-hypertensive effects ( Hypertension. 2015; 65: 784-792; 2016; 29: 258-265 ). We have also shown that norepinephrine (NE) by activating cPLA 2 releases AA, and production of prostanoids in vascular smooth muscle cells ( J Biol Chem. 1996; 217:30149-30157; J. Pharmacol. Exp. Ther. 1993; 266: 1113–1124 ). This study was conducted to determine the contribution of cPLA 2 α in NE-induced hypertension. Eight weeks old male wild-type (cPLA 2 α +/+ ) and cPLA 2 α gene disrupted (cPLA 2 α -/- ) mice were infused with NE (10 mg/kg/day, s.c.) or its vehicle using mini-osmotic pumps for 2 weeks, and the systolic blood pressure (SBP) was measured by tail-cuff. Infusion of NE increased the SBP in cPLA 2 α +/+ mice (148±3 vs. 118±3 mmHg, P<0.05, n=4-5); but not in cPLA 2 α -/- mice (122±5 mmHg, n=5). The NE-induced increase in SBP was minimized by treatment with AA metabolism inhibitor, 5,8,11,14-eicosatetraynoic acid (ETYA) (25 mg/kg, i.p., every 3 rd day) in cPLA 2 α +/+ mice (125±5 vs. 148±3 mmHg, P<0.05, n=4-5). Prostaglandin (PG) E2-EP1 and EP3 receptor activation that increase blood pressure have been implicated in Ang II-induced hypertension. In our study antagonists of the EP3 receptor (L-798106) (10 mg/kg, i.p. every 3 rd day) decreased the NE-induced increase in SBP (130±5 vs. 148±3 mmHg, P<0.05, n=5/group). These data suggest that cPLA 2 α contributes to NE-induced increase in SBP via cPLA 2 α activation, the release of AA and generation of eicosanoids, most likely PGE2 that exerts pro-hypertensive effects by stimulating EP3 receptors. Therefore, the development of agents that selectively inhibit the cPLA 2 α activity or block EP3 receptors could be useful in treating hypertension and its pathogenesis.


Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Keisuke Okuno ◽  
Satoru Eguchi ◽  
Matthew A Sparks

Angiotensin II (Ang II) signaling via AT1 receptor has been shown to play a critical role in the pathogenesis of hypertension, cardiovascular hypertrophy and fibrosis. We have demonstrated that ADAM17 expressed in vascular smooth muscle cells (VSMC) mediates EGF receptor activation and promotes cardiac hypertrophy and perivascular fibrosis induced by Ang II. It is conceivable that Ang II signaling in VSMCs specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis. In a recent study, deficiency of smooth muscle AT1a receptors results in diminished hypertension and protection from cardiac hypertrophy induced by Ang II. However, we have limited understanding whether smooth muscle AT1a receptors affects hypertensive fibrosis in vasculature. Thus, this study was designed to elucidate the roles of the AT1a receptor in VSMCs in cardiovascular remodeling including fibrosis during Ang II stimulation using VSMC AT1a receptor deficient mice. To delete the AT1a receptor from VSMCs, we crossed C57BL/6 transgenic mouse lines expressing Cre recombinase under the control of the sm22α promoter (KIsm22α-Cre). Male AT1a flox/flox KIsm22α-Cre+/- (SMKO) and Controls (AT1a flox/flox KIsm22α-Cre-/-) mice were infused with Ang II (1 μg/kg/min) for 2 weeks via osmotic mini-pump. In Control mice, Ang II infusion for 2 weeks induced cardiac hypertrophy indicated by heart-to-body weight ratio and echocardiogram. After 2 weeks of Ang II infusion, heart-to-body weight ratios were significantly increased in Control mice compared with AT1a SMKO mice (6.04 versus 4.89, respectively, p=0.032). Cardiac wall hypertrophy was seen in Controls after 2 weeks of Ang II infusion, which was attenuated in AT1a SMKOs. Control mice (n=5) showed vascular medial hypertrophy and perivascular fibrosis, whereas these phenotypic changes were attenuated in SMKO mice (n=4). In conclusion, AT1a receptors from VSMC could mediate Ang II-induced cardiovascular hypertrophy and perivascular fibrosis. Whether the data can be fully explained by the prevention of hypertension remains to be determined, the data contrast to the past manuscript showing a protective effect in AT1a flox/flox S100A4-Cre+/- mice (fibroblast silencing) with Ang II infusion.


2015 ◽  
Vol 36 (6) ◽  
pp. 1059-1074 ◽  
Author(s):  
Xiaoning Han ◽  
Xi Lan ◽  
Qiang Li ◽  
Yufeng Gao ◽  
Wei Zhu ◽  
...  

Prostaglandin E2 EP3 receptor is the only prostaglandin E2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68+ microglia, but increased the number of Ym-1+ M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase–mediated cytotoxicity and proinflammatory responses.


2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Mingming Zhang ◽  
Yuerong Xu ◽  
Jianghong Chen ◽  
Chaoshi Qin ◽  
Jing Liu ◽  
...  

Background. Excessive myocardial oxidative stress could lead to the congestive heart failure. NADPH oxidase is involved in the pathological process of left ventricular (LV) remodeling and dysfunction. β3-Adrenergic receptor (AR) could regulate cardiac dysfunction proved by recent researches. The molecular mechanism of β3-AR regulating oxidative stress, especially NADPH oxidase, remains to be determined. Methods. Cardiac hypertrophy was constructed by the transverse aortic constriction (TAC) model. ROS and NADPH oxidase subunits expression were assessed after β3-AR agonist (BRL) or inhibitor (SR) administration in cardiac hypertrophy. Moreover, the cardiac function, fibrosis, heart size, oxidative stress, and cardiomyocytes apoptosis were also detected. Results. β3-AR activation significantly alleviated cardiac hypertrophy and remodeling in pressure-overloaded mice. β3-AR stimulation also improved heart function and reduced cardiomyocytes apoptosis, oxidative stress, and fibrosis. Meanwhile, β3-AR stimulation inhibited superoxide anion production and decreased NADPH oxidase activity. Furthermore, BRL treatment increased the neuronal NOS (nNOS) expression in cardiac hypertrophy. Conclusion. β3-AR stimulation alleviated cardiac dysfunction and reduced cardiomyocytes apoptosis, oxidative stress, and fibrosis by inhibiting NADPH oxidases. In addition, the protective effect of β3-AR is largely attributed to nNOS activation in cardiac hypertrophy.


Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Malini Seth ◽  
Zhu-Shan Zhang ◽  
Lan Mao ◽  
Jarrett Burch ◽  
Victoria Graham ◽  
...  

Transient receptor potential canonical (TRPC) channels are non-selective cation channels that are activated in response to G-protein coupled receptor activation, depletion of internal stores and mechanical stretch. Recent reports suggest that cardiac TRPC channels mediate calcineurin dependent cardiac hypertrophy, yet few details exist as to the mechanism for activation of these channels. Here, we provide evidence that TRPC1 channels are the dominant TRPC channel in mouse cardiomyocytes and cardiac TRPC1 protein expression is augmented by seven fold following thoracic aortic banding (TAC). In addition, we provide the first loss of function studies to show that mice lacking TRPC1 channels developed significantly less cardiac hypertrophy following pressure overload induced by thoracic aortic banding suggesting that TRPC1 may confer deleterious calcium entry. Whole cell voltage clamp studies of isolated adult cardiomyocytes reveal a non-selective cation current that is induced by pressure overload that is absent in TRPC1−/− cardiomyocytes and in which TRP blockers such as gadolinium, 2-amino biphenyl boric acid and SKF96365 inhibit the TAC induced current. Finally, neonatal cardiomyocytes lacking functional TRPC1 display reduced TRPC current in response to cell stretch or angiotensin-II; the functional consequence of which includes reduced calcium oscillation frequency and reduced BNP expression. These results provide the first loss of function evidence for TRPC1 channels in cardiac hypertrophy and implicate TRPC1 as a stretch activated channel.


2019 ◽  
Vol 20 (18) ◽  
pp. 4634 ◽  
Author(s):  
Ineke Böckmann ◽  
Jonas Lischka ◽  
Beatrice Richter ◽  
Jennifer Deppe ◽  
Anja Rahn ◽  
...  

Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin–angiotensin–aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced Ngal indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced Tgfb and Ctgf, which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis.


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