Adipokine CTRP6 improves PPARγ activation to alleviate angiotensin II-induced hypertension and vascular endothelial dysfunction in spontaneously hypertensive rats

doi:10.1016/j.bbrc.2016.11.102

Biochemical and Biophysical Research Communications

Volume 482, Issue 4, 22 January 2017, Pages 727-734

https://doi.org/10.1016/j.bbrc.2016.11.102 Get rights and content

Highlights

•
Serum CTRP6 was significantly decreased in spontaneously hypertensive rats (SHRs).
•
CTRP6 positively regulated the activation of the ERK1/2 signaling pathway.
•
CTRP6 negatively regulates PPARγ mediated Angiotensin II (AngII) expression.
•
CTRP6 alleviates AngII-induced hypertension and vascular endothelial dysfunction.

Abstract

Angiotensin II (AngII) is the most important component of angiotensin, which has been regarded as a major contributor to the incidence of hypertension and vascular endothelial dysfunction. The adipocytokine C1q/TNF-related protein 6 (CTRP6) was recently reported to have multiple protective effects on cardiac and cardiovascular function. However, the exact role of CTRP6 in the progression of AngII induced hypertension and vascular endothelial function remains unclear. Here, we showed that serum CTRP6 content was significantly downregulated in SHRs, accompanied by a marked increase in arterial systolic pressure and serum AngII, CRP and ET-1 content. Then, pcDNA3.1-mediated CTRP6 delivery or CTRP6 siRNA was injected into SHRs. CTRP6 overexpression caused a significant decrease in AngII expression and AngII-mediated hypertension and vascular endothelial inflammation. In contrast, CTRP6 knockdown had the opposite effect to CTRP6 overexpression. Moreover, we found that CTRP6 positively regulated the activation of the ERK1/2 signaling pathway and the expression of peroxisome proliferator-activated receptor γ (PPARγ), a recently proven negative regulator of AngII, in the brain and vascular endothelium of SHRs. Finally, CTRP6 was overexpressed in endothelial cells, and caused a significant increase in PPARγ activation and suppression in AngII-mediated vascular endothelial dysfunction and apoptosis. The effect of that could be rescued by the ERK inhibitor PD98059. In contrast, silencing CTRP6 suppressed PPARγ activation and exacerbated AngII-mediated vascular endothelial dysfunction and apoptosis. In conclusion, CTRP6 improves PPARγ activation and alleviates AngII-induced hypertension and vascular endothelial dysfunction.

Introduction

Hypertension is the one of most common chronic diseases and one of the most important risk factors for cardio- and cerebro-vascular diseases. The trend of an increase in prevalence is striking in young people, especially in China [1]. A few kinds of 24 h long-acting anti-hypertensive drugs have been applied in the management of blood pressure [2], [3]. However, treatment and control for hypertension are still poor for the high incidence of complications, including vascular diseases or systemic inflammation.

Angiotensin is a vasoconstricting hormone derived from the liver and exists in several forms, including angiotensin I (AngI), AngII, AngIII and AngIV [4], [5]. AngII is the most important component of angiotensin. It plays an important role in the renin–angiotensin system that is an accepted target of drugs for lowering blood pressure [6]. Increasing evidence has revealed that AngII is a major contributor to the incidence of hypertension and vascular endothelial dysfunction [7], [8], [9], [10]. On one hand, AngII increases blood pressure by directly stimulating the G protein and an IP3-dependent mechanism leading to contraction [11]; on the other hand, AngII infusion increases and activates immune cells to promote secretion of pro-inflammatory factors such as C-reactive protein (CRP) and endothelin-1 (ET-1), and then leads to vascular endothelial inflammation and dysfunction [12].

C1q/TNF-related protein 6 (CTRP6) is a member of the CTRP adipocytokine family [13]. As an important CTRP member, CTRP6 also plays an important role in the regulation of energy metabolism and inflammation, and might be a potential therapy target for inflammation-related disorders such as diabetes, tissue fibrosis and certain types of tumors [14], [15]. For instance, CTRP6 induces expression of IL-10 via extracellular regulated protein kinase 1/2 (ERK1/2) activation and might be a potential target for pharmacological drugs in inflammation-related diseases [16]. Besides this, overexpression of CTRP6 improves cardiac function, attenuates cardiac hypertrophy and alleviates cardiac fibrosis [17]. However, the exact role of CTRP6 in the progression of hypertension and vascular endothelial function remains unclear.

In this study, we first detected the serum CTRP6 content in WT rats and spontaneously hypertensive rats (SHRs). We found that serum CTRP6 was significantly downregulated in the SHRs, accompanied by a marked increase in arterial systolic pressure and serum AngII, CRP and ET-1 content. Then, to explore the role of CTRP6 in the regulation of hypertension and vascular epithelial function, pcDNA3.1-mediated CTRP6 delivery was applied in the SHRs. CTRP6 overexpression caused a significant decrease in AngII expression and AngII-mediated hypertension and vascular endothelial inflammation. Moreover, this effect of CTRP6 was likely to be related to peroxisome proliferator-activated receptor γ (PPARγ).

Section snippets

Spontaneously hypertensive rats (SHRs)

WT Wistar rats and SHRs were purchased from the Experimental Animal Center of the Shanghai Academy of Life Sciences (Shanghai, China). The rats were monitored in a stress-free, humidity- (50% ± 5%) and temperature-controlled (22 ± 2 °C) room where they were given food and water ad libitum. All animal procedures were performed in accordance with the guidelines on experiments with live vertebrates that are promulgated by the Ethical Committee of the Medical College of Xi'an Jiaotong University.

Monitoring of blood pressure

SHRs displayed a decreased serum CTRP6 content and central PPARγ activation

To explore the potential effect of CTRP6 on the progression of hypertension, CTRP6 content was assessed in the serum of 40 male WT Wistar rats and 48 male SHRs, the mean arterial systolic pressures of which were respectively 143 and 219 mmHg (Fig. 1A). The results showed that the mean CTRP6 content in SHR serum (1.27 μg/mL) was much less than that in WT serum (1.63 μg/mL) (Fig. 1B). Simultaneously, significantly higher levels of AngII, CRP and ET-1 were found in SHR serum (Fig. 1C–E). Some

Discussion

CTRP6 was recently found to have a protective effect on excessive accumulation of fat, progression of ovarian cancer, arthritis and cardiac fibrosis [16], [17], [21]. These disorders share a common feature in that inflammation contributes partly or mainly to their progression, suggesting that CTRP6 might be a potential beneficial regulator in inflammation-related diseases. In this study, we firstly found that serum CTRP6 was reduced in the SHR model and played a protective role in hypertension

Conflicts

None.

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CTRP6 regulates M1 macrophage polarization via the PPAR-γ/NF-κB pathway and reprogramming glycolysis in recurrent spontaneous abortion
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Aberrant polarization and functions of decidual macrophages are closely related to recurrent spontaneous abortion (RSA). C1q/tumor necrosis factor-related protein 6 (CTRP6) is a member of the adiponectin paralog family, and plays indispensable roles in inflammation, glucose uptake and tumor metastasis. However, the regulatory effect of CTRP6 on macrophage polarization and glycolysis in RSA and the underlying mechanisms have not been fully elucidated. In the present study, we first found that CTRP6 expression was positively correlated with the M1 macrophage marker (CD86) in decidual tissues by dual immunofluorescence analysis. In vitro experiments indicated that CTRP6 could facilitate M1 macrophage activation through the PPAR-γ/NF-κB pathway and manipulate the glycolysis of macrophages. Notably, in addition to silencing CTRP6, treatment with a PPAR-γ agonist (GW1929) inhibited M1 macrophage polarization and rescued embryo absorption in vivo. Taken together, these results identify previously unrevealed functions of CTRP6 in macrophage transformation during RSA.
C1q/tumor necrosis factor-related protein-6 exerts protective effects on myocardial ischemia–reperfusion injury through the modulation of the Akt-GSK-3β-Nrf2 signaling cascade
2023, International Immunopharmacology
C1q/tumor necrosis factor-related protein-6 (CTRP6) is a multifunctional protein that plays a pivotal role in diverse physiological and pathological processes. To date, whether CTRP6 has a role in myocardial ischemia–reperfusion (I/R) injury remains unexplored. This work aimed to investigate the potential role and mechanism of CTRP6 in myocardial I/R injury through in vitro and in vivo experiments. CTRP6 expression was downregulated in hypoxia/reoxygenation (H/R)-treated cardiomyocytes. The apoptosis, oxidative stress, and inflammation in the H/R-treated cardiomyocytes were markedly alleviated by CTRP6 overexpression or exacerbated by CTRP6 silencing. Notably, the overexpression of CTRP6 remarkably ameliorated the myocardial injury, infarction area, cardiac apoptosis, oxidative stress, and inflammation in mice with myocardial I/R injury in vivo. Further investigation revealed that CTRP6 overexpression enhanced the activation of Nrf2 in the H/R-treated cardiomyocytes and the myocardium tissue of mice with myocardial I/R injury. CTRP6 overexpression increased the phosphorylated level of Akt and GSK-3β, and the inhibition of Akt abolished CTRP6-overexpression-elicited Nrf2 activation in the H/R-treated cardiomyocytes. Additionally, the inhibition of Akt or Nrf2 abolished the protective effects of CTRP6 overexpression on the H/R-treated cardiomyocytes. Altogether, CTRP6 had protective effects on myocardial I/R injury via the effects on the Akt-GSK-3β-Nrf2 signaling cascade. Our work recommends CTRP6 as a novel cardioprotective target for the treatment of myocardial I/R injury.
Biochemical and immunological changes in obesity
2021, Archives of Biochemistry and Biophysics
Citation Excerpt :
Among its risk factors are aging, physical inactivity, overweight, excessive consumption of alcoholic beverages and unhealthy diets [115]. Angiotensin is a hormone responsible for vasoconstriction and plays a key role in the renin-angiotensin system [116]. This system is the main regulator of blood pressure, electrolytes and water balance [117], where renin, an enzyme that cleaves the precursor angiotensinogen, will give rise to angiotensin [118].
Obesity is a syndemia that promotes high expenditures for public health, and is defined by the excess of adipose tissue that is classified according to its function and anatomical distribution. In obese people, this tissue generates oxidative stress associated with a chronic inflammatory response, in which there is an imbalance in relation to the release of hormones and adipokines that cause loss of body homeostasis and predisposition to the development of some comorbidities. The purpose of this review is to summarize the main events that occur during the onset and progression of obesity with a special focus on biochemical and immunological changes. Hypertrophied and hyperplasia adipocytes have biomarkers and release adipokines capable of regulating pathways and expressing genes that culminate in the development of metabolic changes, such as changes in energy balance and intestinal microbiota, and the development of some comorbidities, diabetes mellitus, dyslipidemias, arterial hypertension, liver disease, cancer, allergies, osteoporosis, sarcopenia and obstructive sleep apnea. Thus, it is necessary to treat and/or prevent pathology, using traditional methods based on healthy eating, and regular physical and leisure activities.
The C1q/TNF-related proteins (CTRPs) in pathogenesis of obesity-related metabolic disorders: Focus on type 2 diabetes and cardiovascular diseases
2020, Life Sciences
Citation Excerpt :
The abundance of data suggests protective effects CTRP6 on cardiac and cardiovascular function. To support this notion, CTRP6 can attenuate AngII-induced hypertension, and improve vascular endothelial dysfunction via activation of PPARγ, a negative regulator of Angiotensin II (AngII) [73]. AKT phosphorylation results in inhibiting apoptosis and improving cardiac repair.
The growing evidence has been tried to explain and characterize C1q/TNF- related proteins (CTRPs) family as the potential diagnostic or therapeutic targets of obesity-related metabolic disorders such as insulin resistance, type 2 diabetes (T2D), and cardiovascular disorders. However, the underlying mechanism is still obscure. Unraveling the signaling pathways downstream of CTRP family members is of great interest and could certainly be beneficial for finding new insights into therapeutic strategies for improving metabolic abnormalities.
This review focused on the role of CTRP members in the initiation and development of obesity-related metabolic disorders with a focus on T2D and cardiovascular diseases. Here we summarize and discuss the role of CTRPs in the regulation of insulin signaling, inflammatory pathways, and energy metabolism, and other signaling pathways pertinent to the pathogenesis of T2D and cardiovascular diseases. We also review available clinical studies to better elucidate the roles of these potential molecules in the initiation and development of the afore-mentioned disorders.
Chronic central miR-29b antagonism alleviates angiotensin II-induced hypertension and vascular endothelial dysfunction
2019, Life Sciences
Citation Excerpt :
These results demonstrated that inhibition of miR-29b could alleviate Ang II-induced endothelial dysfunction via upregulation of the CTRP6/ERK/PPARγ pathway. C1q/tumor necrosis factor-regulated protein 6 (CTRP6), a subtype of the CTRP adipocytokine family (CTRP1-15), has been implicated in regulating lipid and glucose metabolism, and inflammation [1]. Knockdown of CTRP6 can inhibit adipogenesis of 3T3-L1 adipocytes via lipogenic marker genes and ERK1/2 pathway [15], which indicated that CTRP6 increased the expression of IL-10 in macrophages through ERK1/2 activation, and CTRP6 may provide a new targeting point for molecular-based therapy for inflammatory diseases [16].
Dysregulation of miR-29 has been revealed in multiple diseases, but its role in the development of hypertension and vascular endothelial dysfunction has not been defined. Here, we found that, compared with the wild-type (WT) Wistar rats, miR-29b was robustly upregulated in spontaneously hypertensive rats (SHRs), while CTRP6 was distinctly downregulated. There were two miRNA-responding-elements (MREs) for miR-29 in the 3′-UTR of CTRP6 mRNA, and the luciferase activity assay revealed that miR-29b directly targeted CTRP6 mRNA. Intraventricular injection was applied to deliver the miR-29b mimic or miR-29b inhibitor (4 mg/kg) into SHRs once two weeks from 10th week. Downregulation of miR-29b could increase serum CTRP6 content in SHRs, decrease the arterial systolic pressure, reduce serum concentrations of Ang II and ET-1, and enhance serum NO content. Meanwhile, we demonstrated that inhibition of miR-29b increased the phosphorylation of ERK1/2 to activate PPARγ, an inducer of Ang II. Finally, miR-29b expression was manipulated in, and CTRP6 recombinant protein was applied to incubate with the primary aortic endothelial cells. Inhibition of miR-29b increased CTRP6 expression, improved cell proliferation and migration, suppressed secretion of Ang II and ET-1, and decreased ROS accumulation and LDH release, displaying a similar effect to the CTRP6 recombinant protein. Moreover, the CTRP6 recombinant protein could antagonize the suppressive effect of miR-29b on activation of the ERK/PPARγ axis and function of aortic endothelial cells. In conclusion, miR-29b antagonism can alleviate Ang II-induced hypertension and vascular endothelial dysfunction through activating the CTRP6/ERK/PPARγ axis.
CTRP6 inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration
2018, Biomedicine and Pharmacotherapy
Citation Excerpt :
Increasing evidences have reported that CTRP6 was involved in a variety of physiological processes, such as cell proliferation, lipid metabolism, insulin sensitivity, energy balance and cardiac-protection [14–16]. A recent study showed that CTRP6 overexpression significantly inhibited Angiotensin II (AngII)-mediated vascular endothelial dysfunction and apoptosis [17]. However, the effects of CTRP6 on VMSC proliferation and migration remain unknown.
Vascular smooth muscle cell (VSMC) proliferation and migration play critical roles in the development and progression of atherosclerosis. C1q/tumor necrosis factor-related protein 6 (CTRP6), a member of CTRPs family, was involved in cardiovascular diseases, inflammatory reaction and adipogenesis. However, the role of CTRP6 in VSMCs remains largely unknown. The purpose of this study is to investigate the effects of CTRP6 on VSMC proliferation and migration and explore the possible mechanism. Our results indicated that CTRP6 expression was dramatically down-regulated in human atherosclerotic tissues and in cultured VSMCs stimulated by platelet-derived growth factor-BB (PDGF-BB). In addition, CTRP6 overexpression significantly inhibited the proliferation and migration of VSMCs exposed to PDGF-BB, as well as increased expression of α-SMA and SM22α in PDGF-BB-stimulated VSMCs. Furthermore, CTRP6 overexpression efficiently prevented the activation of PI3K/Akt/mTOR in VSMCs in response to PDGF-BB. In conclusion, these findings showed that CTRP6 inhibits PDGF-BB-induced VSMC proliferation and migration, at least in part, through suppressing the PI3K/Akt/mTOR signaling pathway. Therefore, CTRP6 may be a potential target for the treatment of atherosclerosis.

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¹: These authors contributed equally to this study.

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Adipokine CTRP6 improves PPARγ activation to alleviate angiotensin II-induced hypertension and vascular endothelial dysfunction in spontaneously hypertensive rats

Highlights

Abstract

Introduction

Section snippets

Spontaneously hypertensive rats (SHRs)

Monitoring of blood pressure

SHRs displayed a decreased serum CTRP6 content and central PPARγ activation

Discussion

Conflicts

J. Mol. Cell. Cardiol.

Trends Endocrinol. Metabolism

Trends Endocrinol. Metabolism

Mol. Cells

Cell. Signal.

Prevalence of hypertension in China: a cross-sectional study

PloS one

Application of thermal analysis in the characterization of anti-hypertensive drugs

J. Therm. Anal. Calorim.

Taste and hypertension in humans

Curr. Pharm. Des.

Circulating versus local renin-angiotensin system in cardiovascular homeostasis

Circulation

Hypertension, angiotensin, and stroke: beyond blood pressure

Stroke

Role of the NADPH oxidases in the subfornical organ in angiotensin II–induced hypertension

Hypertension

Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses

J. Hypertens.

Cooperative role of mineralocorticoid receptor and caveolin-1 in regulating the vascular response to low nitric oxide–high angiotensin ii–induced cardiovascular injury

J. Pharmacol. Exp. Ther.

Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension

Antioxidants redox Signal.

Endothelin-1, oxidative stress, and endogenous angiotensin ii mechanisms of angiotensin ii type i receptor autoantibody–enhanced renal and blood pressure response during pregnancy

Hypertension