Stachydrine protects eNOS uncoupling and ameliorates endothelial dysfunction induced by homocysteine

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Abstract

Background

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVDs). Stachydrine (STA) is an active component in Chinese motherwort Leonurus heterophyllus sweet, which has been widely used for gynecological and cardiovascular disorders. This study is aimed to examine the effects of STA on homocysteine (Hcy)-induced endothelial dysfunction.

Methods

The effects of STA on vascular relaxation in rat thoracic aortas (TA), mesenteric arteries (MA) and renal arteries (RA) were measured by using Multi Myograph System. The levels of nitric oxide (NO), tetrahydrobiopterin (BH4) and guanosine 3′, 5′ cyclic monophosphate (cGMP) were determined. Endothelial nitric oxide synthase (eNOS) dimers and monomers were assayed by using Western blotting. GTP cyclohydrolase 1 (GTPCH1) and dihydrofolate reductase (DHFR) expressions were measured by using quantitative reverse transcriptase-PCR (qRT-PCR) and Western blotting.

Results

STA effectively blocked Hcy-induced impairment of endothelium-dependent vasorelaxation in rat TA, MA and RA. STA-elicited arterial relaxations were reduced by NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the NO-sensitive guanylyl cyclase inhibitor 1H- [1, 2, 4] Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), but not by inducible iNOS inhibitor 1400 W nor the nonselective COX inhibitor indomethacin. Hcy caused eNOS uncoupling and decreases in NO, cGMP and BH4, which were attenuated by STA. Moreover, STA prevented decreases of GTPCH1 and DHFR levels in Hcy-treated BAECs.

Conclusion

We demonstrated that STA effectively reversed the Hcy-induced endothelial dysfunction and prevented eNOS uncoupling by increasing the expression of GTPCH1 and DHFR. These results revealed a novel mechanism by which STA exerts its beneficial vascular effects.

Electronic supplementary material

The online version of this article (10.1186/s10020-018-0010-0) contains supplementary material, which is available to authorized users.

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Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength?

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Diabetes mellitus is a chronic condition that occurs when the body cannot produce enough or effectively use of insulin. Compared with individuals without diabetes, patients with type 2 diabetes mellitus have a considerably higher risk of cardiovascular morbidity and mortality, and are disproportionately affected by cardiovascular disease. Most of this excess risk is it associated with an augmented prevalence of well-known risk factors such as hypertension, dyslipidaemia and obesity in these patients. However the improved cardiovascular disease in type 2 diabetes mellitus patients can not be attributed solely to the higher prevalence of traditional risk factors. Therefore other non-traditional risk factors may be important in people with type 2 diabetes mellitus. Cardiovascular disease is increased in type 2 diabetes mellitus subjects due to a complex combination of various traditional and non-traditional risk factors that have an important role to play in the beginning and the evolution of atherosclerosis over its long natural history from endothelial function to clinical events. Many of these risk factors could be common history for both diabetes mellitus and cardiovascular disease, reinforcing the postulate that both disorders come independently from "common soil". The objective of this review is to highlight the weight of traditional and non-traditional risk factors for cardiovascular disease in the setting of type 2 diabetes mellitus and discuss their position in the pathogenesis of the excess cardiovascular disease mortality and morbidity in these patients.

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Vascular nitric oxide: Beyond eNOS.

Yingzi Zhao, Paul M. Vanhoutte, Susan Leung (2015)

As the first discovered gaseous signaling molecule, nitric oxide (NO) affects a number of cellular processes, including those involving vascular cells. This brief review summarizes the contribution of NO to the regulation of vascular tone and its sources in the blood vessel wall. NO regulates the degree of contraction of vascular smooth muscle cells mainly by stimulating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), although cGMP-independent signaling [S-nitrosylation of target proteins, activation of sarco/endoplasmic reticulum calcium ATPase (SERCA) or production of cyclic inosine monophosphate (cIMP)] also can be involved. In the blood vessel wall, NO is produced mainly from l-arginine by the enzyme endothelial nitric oxide synthase (eNOS) but it can also be released non-enzymatically from S-nitrosothiols or from nitrate/nitrite. Dysfunction in the production and/or the bioavailability of NO characterizes endothelial dysfunction, which is associated with cardiovascular diseases such as hypertension and atherosclerosis.

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Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities.

T P Tim Cushnie, Benjamart Cushnie, Andrew Lamb (2014)

With reports of pandrug-resistant bacteria causing untreatable infections, the need for new antibacterial therapies is more pressing than ever. Alkaloids are a large and structurally diverse group of compounds that have served as scaffolds for important antibacterial drugs such as metronidazole and the quinolones. In this review, we highlight other alkaloids with development potential. Natural, semisynthetic and synthetic alkaloids of all classes are considered, looking first at those with direct antibacterial activity and those with antibiotic-enhancing activity. Potent examples include CJ-13,136, a novel actinomycete-derived quinolone alkaloid with a minimum inhibitory concentration of 0.1 ng/mL against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark that renders Gram-negative pathogens 16- to >32-fold more susceptible to ciprofloxacin. Where available, information on toxicity, structure-activity relationships, mechanisms of action and in vivo activity is presented. The effects of alkaloids on virulence gene regulatory systems such as quorum sensing and virulence factors such as sortases, adhesins and secretion systems are also described. The synthetic isoquinoline alkaloid virstatin, for example, inhibits the transcriptional regulator ToxT in Vibrio cholerae, preventing expression of cholera toxin and fimbriae and conferring in vivo protection against intestinal colonisation. The review concludes with implications and limitations of the described research and directions for future research.

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Author and article information

Contributors

Lei Xiao: +86-029-82655186 , xiaolei0122@xjtu.edu.cn

Nanping Wang: +86-0411-86110233 , nanpingwang2003@yahoo.com

Journal

Journal ID (nlm-ta): Mol Med

Journal ID (iso-abbrev): Mol. Med

Title: Molecular Medicine

Publisher: BioMed Central (London )

ISSN (Print): 1076-1551

ISSN (Electronic): 1528-3658

Publication date (Electronic): 19 March 2018

Publication date PMC-release: 19 March 2018

Publication date Collection: 2018

Volume: 24

Electronic Location Identifier: 10

Affiliations

[1 ]ISNI 0000 0001 0599 1243, GRID grid.43169.39, Cardiovascular Research Center, School of Basic Medical Sciences, , Xi’an Jiaotong University, ; Xi’an, 710061 China

[2 ]ISNI 0000 0000 9558 1426, GRID grid.411971.b, The Advanced Institute for Medical Sciences, , Dalian Medical University, ; Dalian, 116044 China

Article

Publisher ID: 10

DOI: 10.1186/s10020-018-0010-0

PMC ID: 6016886

SO-VID: a0ba4528-c304-4252-9d00-db58ed551095

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 February 2018

Date accepted : 2 March 2018

Funding

Funded by: National Science Foundation of China

Award ID: 31430045

Award ID: 81770497

Award ID: 81470373

Award Recipient : Lei Xiao Nanping Wang

Custom metadata

Keywords: stachydrine,gtpch1,dhfr,enos uncoupling,vasorelaxation

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Keywords: stachydrine, gtpch1, dhfr, enos uncoupling, vasorelaxation

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Stachydrine protects eNOS uncoupling and ameliorates endothelial dysfunction induced by homocysteine

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Abstract

Background

Methods

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Conclusion

Electronic supplementary material

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Most cited references 29

Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength?

Vascular nitric oxide: Beyond eNOS.

Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities.

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Cited by 13

Most referenced authors 458