Inhibition or deletion of angiotensin II type 1 receptor suppresses elastase-induced experimental abdominal aortic aneurysms

Xuan, Haojun; Xu, Baohui; Wang, Wei; Tanaka, Hiroki; Fujimura, Naoki; Miyata, Masaaki; Michie, Sara A.; Dalman, Ronald L.

doi:10.1016/j.jvs.2016.12.110

Cited by 38 publications

(44 citation statements)

References 42 publications

(64 reference statements)

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“…During the 8–12th weeks, mice were given Rg3 at a dose of 10 mg/kg i.p. once every 2 days ( Tian et al, 2016 ) with oral gavage of GW9662 at 3 mg/kg per day ( Xuan et al, 2017 ). The experimental protocol complied with the Animal Management Rules of the Chinese Ministry of Health (documentation 55, 2001) and was approved by the Animal Ethics Committee of Shandong University.…”

Section: Methodsmentioning

confidence: 99%

Ginsenoside Rg3 Mitigates Atherosclerosis Progression in Diabetic apoE–/– Mice by Skewing Macrophages to the M2 Phenotype

et al. 2018

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Atherosclerosis (AS) in diabetic patients is often associated with low stability, which might be largely attributed to unfavorable macrophage polarization and increased inflammatory response induced by hyperglycaemia. Ginsenoside Rg3 is one of the main active principles of Panax Ginseng, which has been reported to be a natural ligand of peroxisome proliferator-activated receptor-gamma (PPARγ), a key nuclear transcriptional factor involved in inflammation and macrophage differentiation. However, it remains unclear if Rg3 could exert protective effects on plaque stability in diabetes. In this study, we investigated the role of ginsenoside 20(S)-Rg3 in macrophage polarization and AS plaque stability using advanced glycation end products-treated macrophages and diabetic AS mice models. In vitro, advanced glycation end products (AGEs) treatment promoted the expression of proinflammatory molecules and M1 surface markers, whereas 20(S)-Rg3 could reverse the M1 polarization to the M2 phenotype. In vivo, the administration of 20(S)-Rg3 promoted AS lesion stability and reduced the plaque burden, accompanied by increased M2 macrophages and reduced M1 macrophages. In addition, PPARγ antagonist GW9662 co-administration mostly blocked these effects, suggesting the important role of PPARγ pathways in mediating 20(S)-Rg3 effects in macrophage polarization and atherosclerosis progression. Together, these results demonstrated an immunomodulatory role of ginsenoside 20(S)-Rg3 in promoting macrophages to a profile of the M2 type through PPARγ-dependent mechanisms, and indicated a potential role of 20(S)-Rg3 in the prevention and treatment of diabetic atherosclerosis.

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Section: Methodsmentioning

confidence: 99%

Ginsenoside Rg3 Mitigates Atherosclerosis Progression in Diabetic apoE–/– Mice by Skewing Macrophages to the M2 Phenotype

et al. 2018

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“…Elastase-induced AAA in rats was prevented by ACE inhibitors but not by losartan (588). In the mouse model, however, AAA was prevented by AT 1A R deletion or an ARB, telmisartan (1182). Whether calcium chloride-induced AAA is also prevented by ARB remains unclear.…”

Section: E Abdominal Aortic Aneurysmmentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

787

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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“…During the 6th‐10th weeks, mice were given Rg3 at a dose of 10 mg/kg i.p. once 2 days,25 with oral gavage of GW9662 at 3 mg/kg per day 26…”

Section: Methodsmentioning

confidence: 99%

Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis

Guo

Xiao

et al. 2018

J Cellular Molecular Medi

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Ginsenoside 20(R/S)‐Rg3, as a natural peroxisome proliferator‐activated receptor gamma (PPARγ) ligand, has been reported to exhibit differential biological effects. It is of great interest to understand the stereochemical selectivity of 20(R/S)‐Rg3 and explore whether differential PPARγ activation by Rg3 stereoisomers, if it exists, could lead to differential physiological outcome and therapeutic effects in diabetic atherosclerosis. Here, we investigated the binding modes of 20(R/S)‐Rg3 stereoisomers in the PPARγ ligand‐binding domain (PPARγ‐LBD) using molecular modelling and their effects on smooth muscle cell proliferation and migration induced by advanced glycation end products (AGEs). The results revealed that 20(S)‐Rg3 exhibited stronger antiproliferative and antimigratory effects due to stronger PPARγ activation. To validate the in vitro results, we used a mice model with diabetic atherosclerosis and obtained that 20(S)‐Rg3 markedly reduced the plaque size secondary to reducing the proliferation and migration of VSMCs, while the plaques were more stable due to improvements in other plaque compositions. The results shed light on the structural difference between Rg3 stereoisomers that can lead to significant differential physiological outcome, and the (S)‐isomer seems to be the more potent isomer to be developed as a promising drug for diabetic atherosclerosis.

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Inhibition or deletion of angiotensin II type 1 receptor suppresses elastase-induced experimental abdominal aortic aneurysms

Cited by 38 publications

References 42 publications

Ginsenoside Rg3 Mitigates Atherosclerosis Progression in Diabetic apoE–/– Mice by Skewing Macrophages to the M2 Phenotype

Ginsenoside Rg3 Mitigates Atherosclerosis Progression in Diabetic apoE–/– Mice by Skewing Macrophages to the M2 Phenotype

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Ginsenoside Rg3 stereoisomers differentially inhibit vascular smooth muscle cell proliferation and migration in diabetic atherosclerosis

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