Hexarelin suppresses high lipid diet and vitamin D3-induced atherosclerosis in the rat

Pang, Jinjiang; Xu, Qiang; Xu, Xiangbin; Yin, Hongchao; Xu, Ruiyi; Guo, Songjun; Wu, Hao; Wang, Luya; Chen, Chen; Cao, Ji-Min

doi:10.1016/j.peptides.2009.11.007

Cited by 49 publications

(35 citation statements)

References 55 publications

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“…The hexarelin-increased NO levels in SHR in this experiment might play a role in decreasing blood pressure in SHRs. It has also been reported that NO synthesis is impaired in hypertension (7) and in SHRs (17), and hexarelin increases serum NO levels in atherosclerotic rats (23). Ghrelin also increases endothelial NO synthase activation and NO production in endothelial cells (37).…”

Section: Discussionmentioning

confidence: 93%

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Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Fan

Pang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.

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Section: Discussionmentioning

confidence: 93%

“…Intra-assay and interassay variability were 5-9% and 6 -15%, respectively. Serum nitric oxide (NO) concentration was measured with a NO assay kit (Nanjing Jiancheng Biotechnique Institute, Nanjing, China) (23). This assay involves the conversion of nitrate to nitrite by the enzyme nitrate reductase.…”

Section: Methodsmentioning

confidence: 99%

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Fan

Pang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…Establishment of an AS model was conducted based on the description by Pang et al 21) . Briefly, SpragueDawley rats were fed vitamin D 3 (700,000 U/kg) via gavage in the first three days, followed by feeding with high lipid chow for 4 months.…”

Section: Establishment Of An As Model and Exposure 1) Model Of Asmentioning

confidence: 99%

Intravenous Administration of Multi‐walled Carbon Nanotubes Affects the Formation of Atherosclerosis in Sprague‐Dawley Rats

Yang

Shen

et al. 2012

Journal of Occupational Health

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Intravenous Administration of Multiwalled Carbon Nanotubes Affects the Formation of Atherosclerosis in Sprague‐Dawley Rats: Yu‐Ying XU, et al. Zhejiang University School of Medicine, China— Background Carbon nanotubes (CNTs) have many potential applications, including as delivery systems for a variety of diagnostic or therapeutic agents. However, it has been suggested that exposure to carbon nano‐materials may be a risk for the development of vascular diseases due to its impact on the vascular endothelium. Materials and Methods Male Sprague‐Dawley rats (180−200 g) were used to generate an atherosclerosis (AS) model, and the effect of intravenous administration of multi‐walled carbon nanotubes (MWCNTs) on AS was studied. To further understand the underlying mechanisms, the effects of exposure of human umbilical vascular endothelial cells (HUVECs) to MWCNTs were examined. Results Exposure to 200 μg/kg MWCNTs aggravated AS in this model. In addition, exposure to 50, 100 and 200 μg/kg MWCNTs increased the calcification of the aorta in the model. Short‐term exposure also revealed that 200 μg/kg MWCNTs injured the endothelium in the aorta. MWCNTs disrupted the endothelial tight junction and induced endothelial cell death. Conclusion The results demonstrated that MWCNTs could induce structural and functional changes in the endothelium, probably through vascular endotheliocyte injury, which eventually affected the development of AS in SD rats.

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“…8) Hexarelin, a synthetic analog of ghrelin, shows effects similar to those of ghrelin and is more chemically stable, making it a potential alternative to ghrelin. Its beneficial action on the cardiovascular system has been reported by a lot of research, including inhibition of cardiomyocyte apoptosis, [9][10][11] anti-atherosclerosis, 12,13) improving cardiac output, [14][15][16][17] and suppressing cardiac fibrosis. 18) These effects are considered to be mediated not only by GHSR1a but also by activation of cardiac CD36 receptors.…”

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confidence: 99%

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

Huang

Zhang

et al. 2017

Int. Heart J.

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SummaryHexarelin, a synthetic growth hormone-releasing peptide, has been proven to possess cardioprotective actions through its binding to the growth hormone secretagogue receptor (GHSR) 1a and the non-GHSR receptor CD36. However, its effect on myocardial ischemia/reperfusion (I/R) injury has not been fully clarified in vivo. We aimed to determine whether hexarelin treatment could protect cardiomyocytes from I/R injury and to examine the underlying mechanisms. In vivo hearts of male SD rats underwent 30 minutes of ischemia by left coronary artery ligation followed by reperfusion. The rats were then treated subcutaneously twice daily with hexarelin [100 μg/kg·day], ghrelin [400 μg/ kg·day], or saline for 7 days. Echocardiography, malondialdehyde detection, and histochemical staining were performed after treatment. In addition, Western blot was used to examine the expression levels of IL-1β, IL-1Ra, and IL-1RI. Our study showed that hexarelin treatment improved cardiac systolic function, decreased malondialdehyde production, and increased the number of surviving cardiomyocytes. The beneficial effects of hexarelin treatment were slightly superior to those of equimolar ghrelin treatment. We meanwhile confirmed that hexarelin induced down-regulation of IL-1β expression and up-regulation of IL-1Ra expression in I/R myocardium, which could be neutralized by the GHSR antagonist A cute myocardial infarction, which is caused by a sudden embolism of the coronary arteries, is a leading cause of mortality. As the primary clinical therapy for treatment of myocardial infarction, myocardial reperfusion can also aggravate cardiac injury. 1) Its mechanism includes calcium overload, cardiomyocyte apoptosis, and reactive oxygen species (ROS) accumulation.2-5) Finding a strategy to alleviate myocardial I/R injury has become a hot research field in cardiology.In vivo I/R models can cause regional myocardial I/R injury by ligating the left anterior descending coronary artery, which have been widely used to mimic the process of myocardial infarction and subsequent reperfusion.6) Compared to the in vitro global I/R models, in vivo I/R models can not only reveal changes in hemodynamics, and cardiac structure and function after I/R, but also display the impact of molecules in reperfusion flow on I/R myocardium, such as ROS and inflammation cytokines.7) The in vivo I/R models are more consistent with the pathophysiological process of myocardial I/R injury.Ghrelin, a growth hormone-releasing peptide produced in the stomach, is an endogenous ligand of growth hormone secretagogue receptor (GHSR) 1a. Previous studies have demonstrated the cardioprotective effects of exogenous ghrelin administration. 8) Hexarelin, a synthetic analog of ghrelin, shows effects similar to those of ghrelin and is more chemically stable, making it a potential alternative to ghrelin. Its beneficial action on the cardiovascular system has been reported by a lot of research, including inhibition of cardiomyocyte apoptosis, [9][10][11] anti-atherosclerosis, 12,13) impro...

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Hexarelin suppresses high lipid diet and vitamin D3-induced atherosclerosis in the rat

Cited by 49 publications

References 55 publications

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Intravenous Administration of Multi‐walled Carbon Nanotubes Affects the Formation of Atherosclerosis in Sprague‐Dawley Rats

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

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