scholarly journals Qiliqiangxin Rescues Mouse Cardiac Function by Regulating AGTR1/TRPV1-Mediated Autophagy in STZ-Induced Diabetes Mellitus

2018 ◽  
Vol 47 (4) ◽  
pp. 1365-1376 ◽  
Author(s):  
Jing Tong ◽  
Yan Lai ◽  
Yi-An Yao ◽  
Xue-Jun Wang ◽  
Yu-Shuang Shi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Diabetic Mouse ◽  
Transient Receptor Potential Vanilloid ◽  
Ang Ii ◽  
Diabetic Mice ◽  
Angiotensin Ii Receptor ◽  
Beneficial Effects

Background/Aims: To explore the potential role of qiliqiangxin (QLQX) A traditional Chinese medicine and the involvement of angiotensin II receptor type 1 (AGTR1) and transient receptor potential vanilloid 1 (TRPV1) in diabetic mouse cardiac function. Methods: Intragastric QLQX was administered for 5 weeks after streptozotocin (STZ) treatment. Additionally, Intraperitoneal injections of angiotensin II (Ang II) or intragastric losartan (Los) were administered to assess the activities of AGTR1 and TRPV1. Two-dimensional echocardiography and tissue histopathology were used to assess cardiac function Western blot was used to detect the autophagic biomarkers Such as light chain 3 P62 and lysosomal-associated membrane protein 2 And transmission electron microscopy was used to count the number of autophagosomes. Results: Decreased expression of TRPV1 and autophagic hallmarks and reduced numbers of autophagolysosomes as well as increased expression of angiotensin converting enzyme 1 and AGTR1 were observed in diabetic hearts. Blocking AGTR1 with Los mimicked the QLQX-mediated improvements in cardiac function Alleviated myocardial fibrosis and enabled autophagy Whereas Ang II abolished the beneficial effects of QLQX in wild type diabetic mice but not in TRPV1-/- diabetic mice. Conclusions: QLQX may improve diabetic cardiac function by regulating AGTR1/ TRPV1-mediated autophagy in STZ-induced diabetic mice.

scholarly journals Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells

2014 ◽  
Vol 307 (8) ◽  
pp. R945-R955 ◽  
Author(s):  
Ashwini Saxena ◽  
Martha Bachelor ◽  
Yong H. Park ◽  
Flavia R. Carreno ◽  
T. Prashant Nedungadi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Membrane Trafficking ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Src Kinase ◽  
Receptor Potential ◽  
Family Type ◽  
Transient Receptor Potential Vanilloid ◽  
Ang Ii ◽  
Transient Receptor

Transient receptor potential vanilloid family type 4 (TRPV4) channels are expressed in central neuroendocrine neurons and have been shown to be polymodal in other systems. We previously reported that in the rodent, a model of dilutional hyponatremia associated with hepatic cirrhosis, TRPV4 expression is increased in lipid rafts from the hypothalamus and that this effect may be angiotensin dependent. In this study, we utilized the immortalized neuroendocrine rat hypothalamic 4B cell line to more directly test the effects of angiotensin II (ANG II) on TRPV4 expression and function. Our results demonstrate the expression of corticotropin-releasing factor (CRF) transcripts, for sex-determining region Y (SRY) (male genotype), arginine vasopressin (AVP), TRPV4, and ANG II type 1a and 1b receptor in 4B cells. After a 1-h incubation in ANG II (100 nM), 4B cells showed increased TRPV4 abundance in the plasma membrane fraction, and this effect was prevented by the ANG II type 1 receptor antagonist losartan (1 μM) and by a Src kinase inhibitor PP2 (10 μM). Ratiometric calcium imaging experiments demonstrated that ANG II incubation potentiated TRPV4 agonist (GSK 1016790A, 20 nM)-induced calcium influx (control 18.4 ± 2.8% n = 5 and ANG II 80.5 ± 2.4% n = 5). This ANG II-induced increase in calcium influx was also blocked by 1 μM losartan and 10 μM PP2 (losartan 26.4 ± 3.8% n = 5 and PP2 19.7 ± 3.9% n = 5). Our data suggests that ANG II can increase TRPV4 channel membrane expression in 4B cells through its action on AT1R involving a Src kinase pathway.

scholarly journals Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension

2018 ◽  
Vol 315 (5) ◽  
pp. H1304-H1315 ◽  
Author(s):  
Janice M. Diaz-Otero ◽  
Ting-Chieh Yen ◽  
Courtney Fisher ◽  
Daniel Bota ◽  
William F. Jackson ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Angiotensin Ii ◽  
Mineralocorticoid Receptor ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Receptor Activation ◽  
Myogenic Tone ◽  
Transient Receptor Potential Vanilloid ◽  
Cerebrovascular Function ◽  
Transient Receptor

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16−18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg−1·min−1) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg−1·day−1) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5–14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10−9–10−5 mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10−5 mol/l) and indomethacin (10−4 mol/l). We used GSK2193874 (10−7 mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10−9–10−5 mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension. NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.

scholarly journals The nonselective cation channel TRPV4 inhibits angiotensin II receptors

2020 ◽  
Vol 295 (29) ◽  
pp. 9986-9997
Author(s):  
Nicholas W. Zaccor ◽  
Charlotte J. Sumner ◽  
Solomon H. Snyder
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Trp Channel ◽  
Luciferase Assay ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Transient Receptor

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.

scholarly journals Knockout of TRPA1 exacerbates angiotensin II-induced kidney injury

2019 ◽  
Vol 317 (3) ◽  
pp. F623-F631 ◽  
Author(s):  
Shuangtao Ma ◽  
Yan Zhang ◽  
Kecheng He ◽  
Peijian Wang ◽  
Donna H. Wang
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Kidney Injury ◽  
Receptor Potential ◽  
Protective Role ◽  
Ang Ii ◽  
Arginase 1 ◽  
Induced Apoptosis

Macrophage-mediated inflammation plays a critical role in hypertensive kidney disease. Here, we investigated the role of transient receptor potential ankyrin 1 (TRPA1), a sensor of inflammation, in angiotensin II (ANG II)-induced renal injury. Subcutaneous infusion of ANG II (600 ng·min−1·kg−1) for 28 days was used to induce hypertension and renal injury in mice. The results showed that ANG II-induced hypertensive mice have decreased renal Trpa1 expression ( P < 0.01), whereas ANG II receptor type 1a-deficient hypotensive mice have increased renal Trpa1 expression ( P < 0.05) compared with their normotensive counterparts. ANG II induced similar elevations of systolic blood pressure in Trpa1−/− and wild-type (WT) mice but led to higher levels of blood urea nitrogen ( P < 0.05), serum creatinine ( P < 0.05), and renal fibrosis ( P < 0.01) in Trpa1−/− mice than WT mice. Similarly, ANG II increased both CD68+/inducible nitric oxide synthase+ M1 and CD68+/arginase 1+ M2 macrophages in the kidneys of both Trpa1−/− and WT mice (all P < 0.01), with higher extents in Trpa1−/− mice (both P < 0.01). Compared with WT mice, Trpa1−/− mice had significantly increased expression levels of inflammatory cytokines and their receptors in the kidney. Cultured murine macrophages were stimulated with phorbol 12-myristate 13-acetate, which downregulated gene expression of TRPA1 ( P < 0.01). A TRPA1 agonist, cinnamaldehyde, significantly inhibited phorbol 12-myristate 13-acetate-stimulated expression of IL-1β and chemokine (C-C motif) ligand 2 in macrophages, which were attenuated by pretreatment with a TRPA1 antagonist, HC030031 . Furthermore, activation of TRPA1 with cinnamaldehyde induced apoptosis of macrophages. These findings suggest that TRPA1 may play a protective role in ANG II-induced renal injury, likely through inhibiting macrophage-mediated inflammation.

TRPV4 contributes to stretch-induced hypercontractility and time-dependent dysfunction in the aged heart

2019 ◽  
Author(s):  
◽  
Adam Bruce Veteto
Keyword(s):  
Cardiovascular Disease ◽  
Cardiac Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Time Dependent ◽  
Calcium Handling ◽  
Transient Receptor Potential Vanilloid ◽  
University Of Missouri ◽  
Transient Receptor ◽  
The University

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Aims: Cardiovascular disease remains the greatest cause of mortality in Americans over 65. The stretch-activated Transient Receptor Potential Vanilloid-4 (TRPV4) ion channel is expressed in cardiomyocytes of the aged heart. This investigation tests the hypothesis that TRPV4 alters calcium handling and cardiac function in response to increased ventricular preload and cardiomyocyte stretch.

scholarly journals The Role of the Activation of the TRPV1 Receptor and of Nitric Oxide in Changes in Endothelial and Cardiac Function and Biomarker Levels in Hypertensive Rats

2019 ◽  
Vol 16 (19) ◽  
pp. 3576 ◽  
Author(s):  
Juan Carlos Torres-Narváez ◽  
Israel Pérez-Torres ◽  
Vicente Castrejón-Téllez ◽  
Elvira Varela-López ◽  
Víctor Hugo Oidor-Chan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Transient Receptor Potential ◽  
Cardiac Tissue ◽  
Mechanical Performance ◽  
Isolated Heart ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Alternative Mechanism ◽  
Hypertensive Rats

The purpose of the present study was to analyze the actions of transient receptor potential vanilloid type 1 (TRPV1) agonist capsaicin (CS) and of its antagonist capsazepine (CZ), on cardiac function as well as endothelial biomarkers and some parameters related with nitric oxide (NO) release in L-NG-nitroarginine methyl ester (L-NAME)-induced hypertensive rats. NO has been implicated in the pathophysiology of systemic arterial hypertension (SAHT). We analyzed the levels of nitric oxide (NO), tetrahydrobiopterin (BH4), malondialdehyde (MDA), total antioxidant capacity (TAC), cyclic guanosin monophosphate (cGMP), phosphodiesterase-3 (PDE-3), and the expression of endothelial nitric oxide synthase (eNOS), guanosine triphosphate cyclohydrolase 1 (GTPCH-1), protein kinase B (AKT), and TRPV1 in serum and cardiac tissue of normotensive (118±3 mmHg) and hypertensive (H) rats (165 ± 4 mmHg). Cardiac mechanical performance (CMP) was calculated and NO was quantified in the coronary effluent in the Langendorff isolated heart model. In hypertensive rats capsaicin increased the levels of NO, BH4, cGMP, and TAC, and reduced PDE-3 and MDA. Expressions of eNOS, GTPCH-1, and TRPV1 were increased, while AKT was decreased. Capsazepine diminished these effects. In the hypertensive heart, CMP improved with the CS treatment. In conclusion, the activation of TRPV1 in H rats may be an alternative mechanism for the improvement of cardiac function and systemic levels of biomarkers related to the bioavailability of NO.

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