Angiotensin-converting enzyme 2 attenuates oxidative stress and VSMC proliferation via the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways

Persistent hyperglycemia in type 1 diabetes triggers numerous signaling pathways, which may prove deleterious to the endothelium. Since hyperglycemia damages the endothelial layer via multiple signaling pathways, including enhanced oxidative stress, downregulation of angiotensin-converting enzyme2 signaling, and exacerbation of endoplasmic reticulum stress, etc.; hence it becomes difficult to prevent the injury using monotherapy. Thus, the present study was conceived to evaluate the combined effect of endoplasmic reticulum stress inhibition along with angiotensin-converting enzyme-2 activation, two major contributors to hyperglycemia-induced endothelial dysfunction, in preventing endothelial dysfunction associated with type 1 diabetes. Streptozotocin-induced diabetic animals were treated with either diminazene aceturate (5 mg kg-day-1, p.o.) or tauroursodeoxycholic acid, sodium salt (200 mg kg- day-1 i.p.), or both for four weeks. Endothelial dysfunction was evaluated using vasoreactivity assay, where acetylcholine-induced relaxation was assessed in phenylephrine pre-contracted rings. Combination therapy significantly improved vascular relaxation when compared to diabetic control as well as monotherapy. Restoration of nitrite levels along with prevention of collagen led to improved vasodilatation. Moreover, there was an overall reduction in aortic oxidative stress. We conclude that by simultaneously inhibiting ER stress and activating angiotensin-converting enzyme-2 deleterious effects of hyperglycemia on endothelium were significantly alleviated. This could serve as a novel strategy for the prevention of endothelial dysfunction.

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Shen-Kang protects 5/6 nephrectomized rats against renal injury by reducing oxidative stress through the MAPK signaling pathways

International Journal of Molecular Medicine ◽

10.3892/ijmm.2015.2328 ◽

2015 ◽

Vol 36 (4) ◽

pp. 975-984 ◽

Cited By ~ 5

Author(s):

MEIYOU LIU ◽

JISOO PARK ◽

XIAOXIAO WU ◽

YUWEN LI ◽

QUANGDON TRAN ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Renal Injury ◽

Mapk Signaling ◽

Mapk Signaling Pathways

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Overexpression of Central ACE2 (Angiotensin-Converting Enzyme 2) Attenuates the Pressor Response to Chronic Central Infusion of Ang II (Angiotensin II)

Hypertension ◽

10.1161/hypertensionaha.120.15681 ◽

2020 ◽

Vol 76 (5) ◽

pp. 1514-1525

Author(s):

Anyun Ma ◽

Lie Gao ◽

Ahmed M. Wafi ◽

Li Yu ◽

Tara Rudebush ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Angiotensin Converting Enzyme ◽

Pressor Response ◽

Rostral Ventrolateral Medulla ◽

Ventrolateral Medulla ◽

Ang Ii ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Intracerebroventricular Infusion

We investigated the mechanism by which ACE2 (angiotensin-converting enzyme 2) overexpression alters neurohumoral outflow and central oxidative stress. Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is a master antioxidant transcription factor that regulates cytoprotective and antioxidant genes. We hypothesized that upregulation of central ACE2 inhibits the pressor response to Ang II (angiotensin II) by reducing reactive oxygen species through a Nrf2/antioxidant enzyme–mediated mechanism in the rostral ventrolateral medulla. Synapsin human Angiotensin Converting Enzyme 2 positive (SynhACE2 +/+ ) mice and their littermate controls synhACE2 −/− were used to evaluate the consequence of intracerebroventricular infusion of Ang II. In control mice, Ang II infusion evoked a significant increase in blood pressure and norepinephrine excretion, along with polydipsia and polyuria. The pressor effect of central Ang II was completely blocked in synhACE2 +/+ mice. Polydipsia, norepinephrine excretion, and markers of oxidative stress in response to central Ang II were also reduced in synhACE2 +/+ mice. The MasR (Mas receptor) agonist Ang 1–7 and blocker A779 had no effects on blood pressure. synhACE2 +/+ mice showed enhanced expression of Nrf2 in the rostral ventrolateral medulla which was blunted following Ang II infusion. Ang II evoked nuclear translocation of Nrf2 in cultured Neuro 2A (N2A) cells. In synhACE2 −/− mice, the central Ang II pressor response was attenuated by simultaneous intracerebroventricular infusion of the Nrf2 activator sulforaphane; blood pressure was enhanced by knockdown of Nrf2 in the rostral ventrolateral medulla in Nrf2 floxed (Nrf2 f/f ) mice. These data suggest that the hypertensive effects of intracerebroventricular Ang II are attenuated by selective overexpression of brain synhACE2 and may be mediated by Nrf2-upregulated antioxidant enzymes in the rostral ventrolateral medulla.

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Myricetin Protects Cells against Oxidative Stress-Induced Apoptosis via Regulation of PI3K/Akt and MAPK Signaling Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms11114348 ◽

2010 ◽

Vol 11 (11) ◽

pp. 4348-4360 ◽

Cited By ~ 67

Author(s):

Kyoung Ah Kang ◽

Zhi Hong Wang ◽

Rui Zhang ◽

Mei Jing Piao ◽

Ki Cheon Kim ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Mapk Signaling ◽

Induced Apoptosis ◽

Mapk Signaling Pathways

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Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways

Journal of Biological Chemistry ◽

10.1074/jbc.m109.056838 ◽

2009 ◽

Vol 284 (46) ◽

pp. 31972-31981 ◽

Cited By ~ 99

Author(s):

Weihong Yin ◽

Jong-In Park ◽

Richard F. Loeser

Keyword(s):

Oxidative Stress ◽

Growth Factor ◽

Signaling Pathways ◽

Mapk Signaling ◽

Differential Regulation ◽

Proteoglycan Synthesis ◽

Insulin Like Growth Factor ◽

Phosphatidylinositol 3 Kinase ◽

Factor I ◽

Mapk Signaling Pathways

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Weaning Induced Hepatic Oxidative Stress, Apoptosis, and Aminotransferases through MAPK Signaling Pathways in Piglets

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/4768541 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 26

Author(s):

Zhen Luo ◽

Wei Zhu ◽

Qi Guo ◽

Wenli Luo ◽

Jing Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Redox Status ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Control Group ◽

Hepatic Oxidative Stress ◽

Mitogen Activated Protein ◽

D 20 ◽

Mapk Signaling Pathways

This study investigated the effects of weaning on the hepatic redox status, apoptosis, function, and the mitogen-activated protein kinase (MAPK) signaling pathways during the first week after weaning in piglets. A total of 12 litters of piglets were weaned at d 21 and divided into the weaning group (WG) and the control group (CG). Six piglets from each group were slaughtered at d 0 (d 20, referred to weaning), d 1, d 4, and d 7 after weaning. Results showed that weaning significantly increased the concentrations of hepatic free radicals H2O2and NO, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), while significantly decreasing the inhibitory hydroxyl ability (IHA) and glutathione peroxidase (GSH-Px), and altered the level of superoxide dismutase (SOD). The apoptosis results showed that weaning increased the concentrations of caspase-3, caspase-8, caspase-9 and the ratio of Bax/Bcl-2. In addition, aspartate aminotransferase transaminase (AST) and alanine aminotransferase (ALT) in liver homogenates increased after weaning. The phosphorylated JNK and ERK1/2 increased, while the activated p38 initially decreased and then increased. Our results suggested that weaning increased the hepatic oxidative stress and aminotransferases and initiated apoptosis, which may be related to the activated MAPK pathways in postweaning piglets.

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