Apelin/Elabela-APJ: a novel therapeutic target in the cardiovascular system

Liu, Wei; Yan, Jialong; Pan, Weinan; Tang, Mengjie

doi:10.21037/atm.2020.02.07

Cited by 69 publications

(65 citation statements)

References 103 publications

(127 reference statements)

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“…Apart from the putative receptor protein related to the angiotensin receptor AT1 endogenous ligand (Apelin), ELA has been regarded as the second endogenous ligand for a kind of orphaned G protein-coupled receptor called APJ (Apelin receptor, APLNR) [ 23 ]. The ELA/APJ system is relevant to multiple biological functions, such as mesodermal differentiation, cardiogenesis, and treatment targets for heart diseases [ 24 – 26 ]. Ho et al discovered that ELA protected human embryonic stem cells against cellular stress and enhanced their self-renewal ability through PI3K/AKT pathway [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

ELABELA ameliorates hypoxic/ischemic-induced bone mesenchymal stem cell apoptosis via alleviation of mitochondrial dysfunction and activation of PI3K/AKT and ERK1/2 pathways

Chen

Liu

et al. 2020

Stem Cell Res Ther

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Background Mesenchymal stem cells (MSCs) have exerted their brilliant potential to promote heart repair following myocardial infarction. However, low survival rate of MSCs after transplantation due to harsh conditions with hypoxic and ischemic stress limits their therapeutic efficiency in treating cardiac dysfunction. ELABELA (ELA) serves as a peptide hormone which has been proved to facilitate cell growth, survival, and pluripotency in human embryonic stem cells. Although ELA works as an endogenous ligand of a G protein-coupled receptor APJ (Apelin receptor, APLNR), whether APJ is an essential signal for the function of ELA remains elusive. The effect of ELA on apoptosis of MSCs is still vague. Objective We studied the role of ELABELA (ELA) treatment on the anti-apoptosis of MSCs in hypoxic/ischemic (H/I) conditions which mimic the impaired myocardial microenvironment and explored the possible mechanisms in vitro. Methods MSCs were obtained from donated rats weighing between 80~120 g. MSCs were exposed to serum-free and hypoxic (1% O2) environments for 24 h, which mimics hypoxic/ischemic damage in vivo, using serum-containing normoxic conditions (20% O2) as a negative control. MSCs that were exposed to H/I injury with ELA processing were treated by 5 μM of ELA. Cell viability and apoptosis of MSCs were evaluated by CCK8 and flow cytometry, respectively. Mitochondrial function of MSCs was also assessed according to mitochondrial membrane potential (MMP) and ATP content. The protein expression of key kinases of the PI3K/AKT and ERK1/2 signaling pathways involving t-AKT, p-AKT, t-ERK1/2, and p-ERK1/2, as well as apoptosis-related protein expression of Bcl-2, Bax, and cleaved Caspase 3, were monitored by Western blot. Results We found that ELA treatment of H/I-induced MSCs improved overall cell viability, enhanced Bcl/Bax expression, and decreased Caspase 3 activity. ELA inhibited H/I-induced mitochondrial dysfunction by increasing ATP concentration and suppressing the loss of mitochondrial transmembrane potential. However, this anti-apoptotic property of ELA was restrained in APJ-silenced MSCs. Additionally, ELA treatment induced the phosphorylation of AKT and ERK, while the blockade of PI3K/AKT and ERK1/2 pathways with respective inhibitors, LY294002 and U0126, suppressed the action of ELA. Conclusion ELA positively affected on the survival of MSCs and exhibited anti-apoptotic characteristics when exposed to hypoxic/ischemic condition in vitro. Also, the function of ELA was correlated with the APJ receptor, reduced mitochondrial damage, and activation of the PI3K/AKT and ERK1/2 signal axes.

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Section: Introductionmentioning

confidence: 99%

ELABELA ameliorates hypoxic/ischemic-induced bone mesenchymal stem cell apoptosis via alleviation of mitochondrial dysfunction and activation of PI3K/AKT and ERK1/2 pathways

Chen

Liu

et al. 2020

Stem Cell Res Ther

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“…A common modulator of both the PI3K/AKT and the NO/cGMP/PKG signalling cascades in the VSMC is Apelin [63]. Apelin stimulates the NO pathway to induce vasodilation and the PI3K/Akt pathway to induce proliferation and migration of VSMCs [64]. Due to its cardioprotective effects in the VSMC's, Apelin has been suggested as a novel therapeutic target in the cardiovascular system [64].…”

Section: Kcc In Vascular Cellsmentioning

confidence: 99%

“…Apelin stimulates the NO pathway to induce vasodilation and the PI3K/Akt pathway to induce proliferation and migration of VSMCs [64]. Due to its cardioprotective effects in the VSMC's, Apelin has been suggested as a novel therapeutic target in the cardiovascular system [64]. In 2013, researchers found that Apelin stimulated KCC activity through the NO pathway by 336% and 142% by the MAPK/PI3K pathway [65].…”

Section: Kcc In Vascular Cellsmentioning

confidence: 99%

Role of the Cation-chloride-cotransporters in Cardiovascular Disease

Azlan

Zhang

2020

Preprint

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The SLC12 family of cation-chloride-cotransporters (CCCs), comprising potassium chloride cotransporters (KCCs)-mediated Cl- extrusion relative to sodium chloride cotransporters (NKCCs)-mediated Cl- loading, play vital roles in cell volume regulation and ion homeostasis. These functions of the CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells along with their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promote the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings even suggest hypothalamic signalling as a key signalling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.

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“…A common modulator of both the PI3K/AKT and the NO/cGMP/PKG signaling cascades in the VSMCs is Apelin [ 70 ]. Apelin stimulates the NO pathway to induce vasodilation and the PI3K/Akt pathway to induce proliferation and migration of VSMCs [ 71 ]. Due to its cardioprotective effects in the VSMC’s, Apelin has been suggested as a novel therapeutic target in the cardiovascular system [ 71 ].…”

Section: Role Of Kccs In Cardiovascular Diseasementioning

confidence: 99%

“…Apelin stimulates the NO pathway to induce vasodilation and the PI3K/Akt pathway to induce proliferation and migration of VSMCs [ 71 ]. Due to its cardioprotective effects in the VSMC’s, Apelin has been suggested as a novel therapeutic target in the cardiovascular system [ 71 ]. In 2013, researchers found that Apelin stimulated KCC activity through the NO pathway by 336% and 142% by the MAPK/PI3K pathway [ 72 ].…”

Section: Role Of Kccs In Cardiovascular Diseasementioning

confidence: 99%

Role of the Cation-Chloride-Cotransporters in Cardiovascular Disease

Azlan

Zhang

2020

Cells

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The SLC12 family of cation-chloride-cotransporters (CCCs) is comprised of potassium chloride cotransporters (KCCs), which mediate Cl− extrusion and sodium-potassium chloride cotransporters (N[K]CCs), which mediate Cl− loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. The functions of CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells in addition to their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promotes the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings suggest hypothalamic signaling as a key signaling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.

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Apelin/Elabela-APJ: a novel therapeutic target in the cardiovascular system

Cited by 69 publications

References 103 publications

ELABELA ameliorates hypoxic/ischemic-induced bone mesenchymal stem cell apoptosis via alleviation of mitochondrial dysfunction and activation of PI3K/AKT and ERK1/2 pathways

ELABELA ameliorates hypoxic/ischemic-induced bone mesenchymal stem cell apoptosis via alleviation of mitochondrial dysfunction and activation of PI3K/AKT and ERK1/2 pathways

Role of the Cation-chloride-cotransporters in Cardiovascular Disease

Role of the Cation-Chloride-Cotransporters in Cardiovascular Disease

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