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1.
Clin Exp Hypertens ; : 1-10, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31851528

RESUMO

Background: Arterial pressure volume index (API) and arterial velocity pulse index (AVI) contribute to the development of vascular damage and cardiovascular disease. However, the relationship between common API/AVI trajectories and cardiovascular outcomes in hypertensive patients with heart failure with preserved ejection fraction (HFpEF) is unknown.Methods: A total of 488 consecutive hypertensive patients with HFpEF who repeatedly underwent API/AVI measurements were prospectively examined. We then applied API/AVI measurements into actual clinical practice. Latent mixture modeling was performed to identify API/AVI trajectories. Hazards ratios (HRs) were measured using Cox proportional hazard models.Results: We identified four distinct API/AVI trajectory patterns: low (7.6%), moderate (43.8%), high (28.9%), and very high (19.7%). Compared with the low group, higher API trajectories were associated with increased risk of total cardiovascular events (high group, adjusted HR: 2.91, 95% confidence interval [CI]: 1.97-4.26; very high group, adjusted HR: 2.46, 95%CI: 1.18-3.79). Consistently, higher AVI trajectories were also associated with a higher risk of total cardiovascular events (high group, adjusted HR: 2.58, 95%CI: 1.23-5.47; very high group, adjusted HR: 3.12, 95%CI: 1.83-6.08), compared with the low trajectory group.Conclusion: High API/AVI trajectories are strong predictors of cardiovascular risk in hypertensive patients with HFpEF. Among these patients, measuring API/AVI may improve risk stratification and provide additional information to tailor treatment strategies.

2.
Curr Hypertens Rev ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721716

RESUMO

BACKGROUND: Salt sensitivity is increased following renal ischemia-reperfusion (I/R) injury. We test the hypothesis that high-salt intake-induced increase in renal sympathetic nerve activity (RSNA) after renal I/R can be prevented by activation of transient receptor potential vanilloid 1 (TRPV1). METHODS: Rats were fed a 0.4% NaCl diet for 5 weeks after renal I/R, followed by a 4% NaCl diet for 4 more weeks in four groups: sham, I/R, I/R+high dose capsaicin (HDC), and I/R+low dose capsaicin (LDC). The low (1mg/kg) or high (100mg/kg) dose of capsaicin was injected subcutaneously before I/R to activate or desensitize TRPV1, respectively. RESULTS: Systolic blood pressure was gradually elevated after fed on high-salt diet in the I/R and I/R+HDC groups but not in the I/R+LDC group, with a greater increase in the I/R+HDC group. Renal function was impaired in the I/R group and was further deteriorated in the I/R+HDC group but was unchanged in the I/R+LDC group. At the end of high salt treatment, afferent renal nerve activity in response to unilateral intra-pelvic administration of capsaicin was decreased in the I/R group and was further suppressed in the I/R+HDC group but was unchanged in the I/R+LDC group. RSNA in response to intrathecal administration of muscimol, a selective agonist of GABA-A receptors, was augmented in the I/R group and further intensified in the I/R+HDC group but was unchanged in the I/R+LDC group. Similarly, urinary norepinephrine levels were increased in the I/R group and was further elevated in the I/R+HDC group but unchanged in the I/R+LDC group. CONCLUSION: These data suggest that TRPV1 activation prevents renal I/R injury-induced increase in salt sensitivity by suppressing RSNA.

3.
Exp Ther Med ; 18(5): 3636-3642, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31602241

RESUMO

This study tests the hypothesis that the lipoxygenase (LOX) pathway mediates protease-activated receptor (PAR) 2-induced activation of the transient receptor potential vanilloid receptor 1 (TRPV1) to protect the heart from ischemia/reperfusion (I/R) injury. SLIGRL, a PAR2 activating peptide, was administered prior to reperfusion following left anterior descending coronary artery ligation in wild type (WT) and TRPV1 knockout (TRPV1-/-) mice. In a Langendorffly perfused heart I/R model, hemodynamic parameters, including left ventricular end-diastolic pressure, left ventricular developed pressure, coronary blood flow and left ventricular peak +dP/dt were evaluated after I/R. SLIGRL reduced the cardiac infarct size in WT and TRPV1-/- mice with a greater effect in the former strain (P<0.05). SLIGRL increased plasma levels of calcitonin gene-related peptide (CGRP) and substance P in WT (both P<0.05) but not in TRPV1-/- mice. Pretreatment with CGRP8-37 (a CGRP receptor antagonist) or RP67580 (a neurokinin-1 receptor antagonist) alone had no effect on SLIGRL-induced cardiac protection in either strain. However, combined administration of CGRP8-37 and RP67580 abolished SLIGRL-induced cardiac protection in WT but not in TRPV1-/- mice. Nordihydroguaiaretic acid (a general LOX inhibitor) and baicalein (a 12-LOX inhibitor), but not indomethacin (a cyclooxygenase inhibitor) and hexanamide (a selective cytochrome P450 epoxygenase inhibitor), abolished the protective effects of SLIGRL in WT (all P<0.05) but not in TRPV1-/- hearts. These data suggested that PAR2, possibly via 12-LOX, activates TRPV1 and leads to CGRP and substance P release to prevent I/R injury in the heart, indicating that the 12-LOX-TRPV1 pathway conveys cardiac protection to alleviate myocardial infarction.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31513001

RESUMO

BACKGROUND: Activation of transient receptor potential vanilloid subtype 1 (TRPV1) channels protects the heart from ischemia/reperfusion (I/R) injury through releasing calcitonin gene-related peptide (CGRP) and substance P (SP). The current study aimed to study the cardioprotective effects of TRPV1 in obesity. METHODS: TRPV1 gene knockout (TRPV1-/-) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet or for 20 weeks, and then the hearts were collected for I/R injury ex vivo. The hearts were mounted on a Langendorff apparatus and subjected to ischemia (30 min) and reperfusion (40 min) after incubated with capsaicin (10 nmol/L), CGRP (0.1 µmol/L), and SP (0.1 µmol/L). Then, coronary flow, left ventricular peak positive dP/dt (+dP/dt), left ventricular developed pressure (LVDP), and left ventricular end-diastolic pressure (LVEDP) were measured. RESULTS: HFD intake remarkably reduced CF, +dP/dt, and LVDP and elevated LVEDP in both strains (P<0.05). Treatment with capsaicin decreased infarct size, increased CF, +dP/dt, and LVDP, and decreased LVEDP in WT mice on control diet (P<0.05), but did not do so in other three groups. Treatment with CGRP and SP decreased infarct size in both strains fed with control diet (P<0.05). In contrast, not all the parameters of cardiac postischemic recovery in HFD-fed WT and TRPV1-/- mice were improved by CGRP and SP. CONCLUSIONS: These results suggest that HFD intake impairs cardiac postischemic recovery. HFD-induced impairment of recovery is alleviated by CGRP in both strains and by SP only in TRPV1-/- mice, indicating that the effects of CGRP and SP are differentially regulated during HFD intake.

5.
In Vivo ; 33(5): 1431-1437, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471389

RESUMO

BACKGROUND/AIM: Transient receptor potential vanilloid 1 (TRPV1)-expressing sensory nerves innervate the pancreatic islets. Sensory neuropeptides, including calcitonin gene-related peptide (CGRP) and substance P (SP), participate in insulin secretion. This study aimed to investigate the role of TRPV1 in glucose-induced insulin secretion. MATERIALS AND METHODS: TRPV1-/- and wild-type (WT) mice were fed a normal diet for 24 weeks. Glucose tolerance and insulin secretion were measured at the end of the experiments. RESULTS: TRPV1-/- mice had greater impairments in glucose tolerance and higher decrease in glucose-induced insulin secretion than WT mice. Capsaicin (a TRPV1 agonist) increased insulin secretion in WT, but not in TRPV1-/- mice. Glucose-induced insulin secretion was blunted in TRPV1-/- mice, and was attenuated by AMG9810 (a TRPV1 inhibitor), CGRP8-37 (a CGRP receptor antagonist), or RP67580 (a NK-1 receptor antagonist) in WT mice. Glucose-induced SP and CGRP release from WT pancreas was higher than that from TRPV1-/- pancreas. CONCLUSION: TRPV1 mediates glucose-induced insulin secretion likely through CGRP and SP release.


Assuntos
Glucose/metabolismo , Secreção de Insulina , Neuropeptídeos/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Intolerância à Glucose , Masculino , Camundongos , Camundongos Knockout , Canais de Cátion TRPV/genética
6.
Am J Physiol Renal Physiol ; 317(3): F623-F631, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31339777

RESUMO

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-1ß 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.

7.
J Magn Reson ; 303: 121-127, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31051387

RESUMO

To map the hemodynamic responses of kidney microstructures at 7.05 T with improved sensitivity, a Wireless Amplified NMR Detector (WAND) with cylindrical symmetry was fabricated as an endoluminal detector that can convert externally provided wireless signal at 600.71 MHz into amplified MR signals at 300.33 MHz. When this detector was inserted inside colonic lumens to sensitively observe adjacent kidneys, it could clearly identify kidney microstructures in the renal cortex and renal medullary. Owing to the higher achievable spatial resolution, differential hemodynamic responses of kidney microstructures under different breathing conditions could be individually quantified to estimate the underlying correlation between oxygen bearing capability and local levels of oxygen unsaturation. The WAND's ability to map Blood Oxygen Level Dependent (BOLD) signal responses in heterogeneous microstructures will pave way for early-stage diagnosis of kidney diseases, without the use of contrast agents for reduced tissue retention and toxicity.

8.
PeerJ ; 7: e6505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30834186

RESUMO

Background: Obesity is a major risk factor for end-stage renal disease. Using transient receptor potential vanilloid 1 knockout (TRPV1-/-) mice, we tested the hypothesis that TRPV1 protects against obesity-induced exacerbation of renal ischemia-reperfusion (I/R) injury. Methods: TRPV1-/- and wild-type (WT) mice were fed a chow or Western diet (WD) for 22-23 weeks. After that, mice were subjected to renal I/R injury, and renal cortical blood flow (CBF) and medullary blood flow (MBF) were measured. Results: The Western diet significantly increased body weight and fasting blood glucose levels in both TRPV1-/- and WT mice. WD-induced impairment of glucose tolerance was worsened in TRPV1-/- mice compared with WT mice. WD intake prolonged the time required to reach peak reperfusion in the cortex and medulla (both P < 0.05), decreased the recovery rate of CBF (P < 0.05) and MBF (P < 0.05), and increased blood urea nitrogen, plasma creatinine, and urinary 8-isoprostane levels after I/R in both mouse strains, with greater effects in TRPV1-/- mice (all P < 0.05). Renal I/R increased calcitonin gene-related peptide (CGRP) release in WT but not in TRPV1-/- mice, and WD attenuated CGRP release in WT mice. Moreover, blockade of CGRP receptors impaired renal regional blood flow and renal function in renal I/R injured WT mice. Conclusion: These results indicate that TRPV1 plays a protective role in WD-induced exacerbation of renal I/R injury probably through enhancing CGRP release and increasing renal blood flow.

9.
Curr Hypertens Rev ; 15(2): 144-153, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30381083

RESUMO

BACKGROUND: This study tested the hypothesis that genetically ablation of transient receptor potential vanilloid type 1 (TRPV1) exacerbates impairment of baroreflex in mice fed a western diet (WD) and leads to distinct diurnal and nocturnal blood pressure patterns. METHODS: TRPV1 gene knockout (TRPV1-/-) and wild-type (WT) mice were given a WD or normal diet (CON) for 4 months. RESULTS: Capsaicin, a selective TRPV1 agonist, increased ipsilateral afferent renal nerve activity in WT but not TRPV1-/- mice. The sensitivity of renal sympathetic nerve activity and heart rate responses to baroreflex were reduced in TRPV1-/--CON and WT-WD and further decreased in TRPV1-/--WD compared to the WT-CON group. Urinary norepinephrine and serum insulin and leptin at day and night were increased in WT-WD and TRPV1-/--WD, with further elevation at night in TRPV1-/--WD. WD intake increased leptin, IL-6, and TNF-α in adipose tissue, and TNF-α antagonist III, R-7050, decreased leptin in TRPV1-/--WD. The urinary albumin level was higher in TRPV1-/--WD than WT-WD. Blood pressure was not different during daytime among all groups, but increased at night in the TRPV1-/--WD group compared with other groups. CONCLUSIONS: TRPV1 ablation leads to elevated nocturnal but not diurnal blood pressure, which is probably attributed to further enhancement of sympathetic drives at night.

11.
Cell Physiol Biochem ; 50(3): 1164-1177, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30355936

RESUMO

BACKGROUND/AIMS: Bleeding complications after percutaneous coronary intervention (PCI) are strongly associated with adverse patient outcomes. However, there are no specific guidelines for the predictors and management of antiplatelet-related bleeding complications in Chinese elderly patients with acute coronary syndrome (ACS). METHODS: A retrospective analysis of 237 consecutive patients (aged ≥ 75 years) with ACS who had undergone successful PCI from January 2010 to December 2016 was performed to identify predictors and management of antiplatelet-related bleeding complications. Multivariate logistic regression analysis was conducted to investigate independent predictors of antiplatelet-related bleeding complications. We defined antiplatelet-related bleeding complications as first hospitalization received long-term oral antiplatelet therapy and required hospitalization, including gastrointestinal and intracranial bleedings. RESULTS: After multivariable adjustment, independent risk predictors of antiplatelet-related bleeding complications included female gender (odds ratio [OR]: 2.96; 95% confidence interval [CI]: 1.98 to 4.15; P = 0.011), body mass index (OR: 1.54; 95% CI: 1.06 to 1.94; P = 0.034), previous history of bleeding (OR: 4.03; 95% CI: 1.84 to 6.12; P = 0.004), fasting blood glucose (OR: 2.79; 95% CI: 1.23 to 4.46; P = 0.025), and chronic total occlusion lesion (OR: 4.69; 95% CI: 2.19 to 7.93; P = 0.007). Of 46 patients with antiplatelet-related bleeding complications, 54.3% were treated short-term dual antiplatelet therapy (DAPT) cessation (0-7 days) and 45.7% underwent long-term DAPT cessation (> 7 days). Among these, 14 patients presented major adverse cardiac and cerebrovascular events (MACCE), whereas no re-bleeding happened over all available follow-up. The incidence of MACCE was not significantly different between the two groups one year after PCI (36.0% for short-term DAPT cessation versus 23.8% for long-term DAPT cessation, P = 0.522). CONCLUSION: For elderly patients with ACS, multiple factors were likely to contribute to antiplatelet-related bleeding complications, especially previous history of bleeding and chronic total occlusion lesion. Better individualized, tailored and risk-adjusted antiplatelet therapy after PCI is urgently needed in this high-risk population.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Hemorragia/etiologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Síndrome Coronariana Aguda/patologia , Idoso , Glicemia , China , Feminino , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação de Plaquetas/efeitos adversos , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
13.
Front Physiol ; 9: 1060, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30116205

RESUMO

Uncoupling protein 2 (UCP2) belongs to the family of mitochondrial anion carrier proteins. It uncouples oxygen consumption from ATP synthesis. UCP2 is ubiquitously expressed in most cell types to reduce oxidative stress. It is tightly regulated at the transcriptional, translational, and post-translational levels. UCP2 in the cardiovascular system is being increasingly recognized as an important molecule to defend against various stress signals such as oxidative stress in the pathology of vascular dysfunction, atherosclerosis, hypertension, and cardiac injuries. UCP2 protects against cellular dysfunction through reducing mitochondrial oxidative stress and modulation of mitochondrial function. In view of the different functions of UCP2 in various cell types that contribute to whole body homeostasis, cell type-specific modification of UCP2 expression may offer a better approach to help understanding how UCP2 governs mitochondrial function, reactive oxygen species production and transmembrane proton leak and how dysfunction of UCP2 participates in the development of cardiovascular diseases. This review article provided an update on the physiological regulation of UCP2 in the cardiovascular system, and also discussed the involvement of UCP2 deficiency and associated oxidative stress in the pathogenesis of several common cardiovascular diseases. Drugs targeting UCP2 expression and activity might serve another effective strategy to ameliorate cardiovascular dysfunction. However, more detailed mechanistic study will be needed to dissect the role of UCP2, the regulation of UCP2 expression, and the cellular responses to the changes of UCP2 expression in normal and stressed situations at different stages of cardiovascular diseases.

14.
Am J Hum Genet ; 103(2): 276-287, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30075114

RESUMO

Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension.


Assuntos
Argininossuccinato Liase/genética , Acidúria Argininossuccínica/genética , Células Endoteliais/patologia , Hipertensão/genética , Adolescente , Animais , Pressão Sanguínea/genética , Células Cultivadas , Criança , Modelos Animais de Doenças , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/genética , Óxido Nítrico/genética , Estresse Oxidativo/genética , Distúrbios Congênitos do Ciclo da Ureia/genética
15.
Kidney Blood Press Res ; 43(4): 1285-1296, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30078015

RESUMO

BACKGROUND/AIMS: High-salt intake after recovery from renal ischemia-reperfusion (I/R) injury leads to hypertension with severe renal damage. Transient receptor potential vanilloid type 1 (TRPV1) channels have been involved in the regulation of inflammation and oxidative stress following ischemic organ injury. We tested the hypothesis that activation of TRPV1 conveys preconditioning protection to the kidney subjected to I/R. METHODS: TRPV1 was activated or down-regulated by subcutaneous injection of a low (1mg/kg) or high (100mg/kg) dose of capsaicin, respectively, 3 hours before ischemia. Rats were fed a 0.4% NaCl diet for 5 weeks after I/R followed by a 4% NaCl diet for 4 more weeks in 4 groups: sham, I/R, I/R+high-dose capsaicin (HCap), and I/R+low-dose capsaicin (LCap). RESULTS: Renal TRPV1 expression was decreased in I/R rats (P< 0.05) and further reduced in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap rats compared with the sham group. Blood pressure were elevated in I/R rats (P< 0.05) and further increased in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap rats compared with sham. Renal function was impaired in I/R rats (P< 0.05) and further deteriorated in I/R+HCap group (P< 0.05) but unchanged in I/R+LCap group. Renal inflammatory responses, oxidative stress, and renal collagen deposition were augmented in I/R rats (all P< 0.05) and further intensified in I/R+HCap group (all P< 0.05) but unchanged in I/R+LCap group. CONCLUSION: Activation of TRPV1 plays an anti-inflammatory and anti-oxidative stress role in preventing renal tissue damage and salt-induced hypertension after I/R injury, indicating that TRPV1 conveys preconditioning protection that may have therapeutic implication.


Assuntos
Lesão Renal Aguda/prevenção & controle , Hipertensão/prevenção & controle , Traumatismo por Reperfusão/complicações , Cloreto de Sódio na Dieta/efeitos adversos , Canais de Cátion TRPV/metabolismo , Animais , Capsaicina/administração & dosagem , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Hipertensão/induzido quimicamente , Inflamação/prevenção & controle , Precondicionamento Isquêmico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras , Ratos , Canais de Cátion TRPV/farmacologia
16.
Hypertens Res ; 41(9): 679-690, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30006640

RESUMO

This study tested the hypothesis that selective ablation of transient receptor potential vanilloid type 1 (TRPV1)-positive nerve fibers by intrathecal injection of resiniferatoxin (RTX) enhances renal sympathoexcitatory responses and salt sensitivity. Intrathecal injection of RTX (1.8 µg/kg) to the levels of lower thoracic and upper lumbar spinal cord (T8-L3) increased mean arterial pressure (MAP) in rats fed a normal (NS, 1% NaCl) or high-sodium (HS, 8% NaCl) diet for 4 weeks compared to vehicle-treated rats (NS: 121 ± 2 vs. 111 ± 2; HS: 154 ± 2 vs. 134 ± 2 mm Hg, both P < 0.05), with a greater increase in HS compared to NS rats (9 ± 1% vs. 15 ± 1%, P < 0.05). TRPV1 contents were decreased in T8-L3 segments of spinal dorsal horn but not in corresponding dorsal root ganglia and the kidney following RTX treatment (P < 0.05). Selective activation of GABA-A receptors with intrathecal T8-L3 segment-injection of muscimol (3 nmol/kg) decreased renal sympathetic nerve activity and increased urinary excretion in both NS and HS rats, with a greater effect in RTX-treated compared to vehicle-treated rats (P < 0.05). Chronic activation of GABA-A receptors with muscimol (50 mg/kg/day × 2, p.o.) abolished RTX treatment-induced pressor effects in NS and HS rats. GAD65/67, a GABA synthetase, in the spinal cord was downregulated and tyrosine hydroxylase in the kidney upregulated in NS or HS rats treated with RTX (P < 0.05). Thus, selective ablation of TRPV1-positive central terminals of sensory neurons plays a prohypertensive role possibly via inhibition of spinal GABA system especially with HS intake, suggesting that activation of TRPV1 in central terminals of sensory neurons may convey an antihypertensive effect.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Diterpenos/farmacologia , Rim/inervação , Cloreto de Sódio na Dieta/administração & dosagem , Sistema Nervoso Simpático/efeitos dos fármacos , Canais de Cátion TRPV/fisiologia , Animais , Capsaicina/farmacologia , Diterpenos/administração & dosagem , Glutamato Descarboxilase/metabolismo , Injeções Espinhais , Masculino , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Canais de Cátion TRPV/análise , Canais de Cátion TRPV/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismo
17.
Cell Physiol Biochem ; 47(2): 817-826, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29807359

RESUMO

BACKGROUND/AIMS: Activation of stromal interaction molecule 1 (STIM1) and Orai1 participates in the development of cardiac hypertrophy. Store-operated Ca2+ entry-associated regulatory factor (SARAF) is an intrinsic inhibitor of STIM1-Orai1 interaction. Thus, we hypothesized that SARAF could prevent cardiac hypertrophy. METHODS: Male C57BL/6 mice, aged 8 weeks, were randomly divided into sham and abdominal aortic constriction surgery groups and were infected with lentiviruses expressing SARAF and GFP (Lenti-SARAF) or GFP alone (Lenti-GFP) via intramyocardial injection. At 4 weeks after aortic constriction, left ventricular structure and function were assessed by echocardiography and hemodynamic assays. The gene and protein expressions of SARAF, STIM1, and Orai1 were measured by quantitative PCR and Western blot, respectively. RESULTS: Gene and protein expressions of SARAF were significantly decreased, while STIM1 and Orai1 were increased in the heart tissue compared with sham group. Overexpression of SARAF in the heart prevented the upregulation of STIM1 and Orai1, and importantly, attenuated aortic constriction-induced decrease in maximal rate of left ventricular pressure decay and increases in thickness of interventricular septum and left ventricular posterior wall, heart weight/body weight ratio, and size of cardiomyocytes. Blood pressure detected through the carotid artery and left ventricular systolic function were not affected by SARAF overexpression. In addition, overexpression of SARAF also attenuated angiotensin II-induced upregulation of STIM1 and Orai1 and hypertrophy of cultured cardiomyocytes. CONCLUSION: Overexpression of SARAF in the heart prevents cardiac hypertrophy, probably through suppressing the upregulation of STIM1/Orai1.


Assuntos
Cardiomegalia/prevenção & controle , Proteínas de Membrana/metabolismo , Proteína ORAI1/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Angiotensina II/farmacologia , Animais , Aorta Abdominal/cirurgia , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Linhagem Celular , Ecocardiografia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Proteína ORAI1/genética , Pressão , Molécula 1 de Interação Estromal/genética , Regulação para Cima/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-29732984

RESUMO

BACKGROUND: Transient Receptor Potential Vanilloid 1 (TRPV1) channels in sensory nerves have anti-oxidative properties and counteract obesity and diabetes that are associated with diastolic dysfunction with preserved ejection fraction. We tested the hypothesis that TRPV1 knockout exacerbates high-fat diet (HFD)-induced glucose intolerance and diastolic dysfunction. METHOD: Trpv1-/- and wild-type (WT) mice were fed chow diet or HFD for 20 weeks. Then, we performed the intraperitoneal glucose tolerance test, measured the heart function through transthoracic echocardiography and Langendorff heart perfusion system, analyzed cardiac histology, and measured the myocardial superoxide production and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. RESULTS: HFD increased body weight, heart weight, and levels of fasting glucose, insulin, and leptin in both strains, with no differences between two strains. HFD impaired glucose tolerance in both strains with a more profound effect on Trpv1-/- than WT mice. HFD increased left ventricular (LV) internal diameter in diastole in both strains, while increased LV posterior wall thickness in diastole in Trpv1-/- but not in WT mice. HFD increased LV end-diastolic pressure in both strains with a further increase in Trpv1-/- mice, while decreased -dP/dt in Trpv1-/- but not in WT mice. HFDinduced cardiac collagen deposition and superoxide production were enhanced in Trpv1-/- mice. HFD upregulated cardiac p22phox in both strains, while increased p47phox in Trpv1-/- but not in WT mice. CONCLUSION: In summary, TRPV1 knockout exacerbates HFD-induced glucose intolerance, cardiac oxidative stress and collagen deposition, leading to aggravated LV diastolic dysfunction.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Canais de Cátion TRPV/genética , Disfunção Ventricular Esquerda/genética , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Canais de Cátion TRPV/metabolismo , Disfunção Ventricular Esquerda/patologia
19.
Biomed Pharmacother ; 99: 261-270, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29334670

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) channels expressed in sensory nerves may regulate vascular tone and cardiovascular function via their anti-inflammatory effects by releasing neuropeptide calcitonin gene-related peptide (CGRP). Inflammation plays a role in the progression of cardiac hypertrophy and TRPV1 activation may be key to cardiac inflammatory processes. The aim of this study was to test the hypothesis that TRPV1 modulates inflammatory processes to protect the heart from pressure overload-induced hypertrophy and inflammatory responses. Trpv1 knockout (Trpv1-/-) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) or sham operation. Four weeks after TAC, WT and Trpv1-/- mice had developed left ventricular (LV) hypertrophy with increased LV mass, fibrosis and infiltration of macrophages as well as increased secretion of tumor necrosis factor α, interleukin-6 from cardiac tissue (all P < 0.05), those were higher in Trpv1-/- than in WT mice with TAC (all P < 0.05). In addition, decreases of LV ejection fraction and fractional shortening were greater in Trpv1-/- than in WT mice (both P < 0.05). Moreover, atrial natriuretic peptide level was greater in Trpv1-/- than in WT mice with TAC (P < 0.05). Compared to sham control, TAC procedure significantly increased cardiac TRPV1 expression and CGRP release in WT mice (both P < 0.05), but not in Trpv1-/- mice. These results demonstrate that Trpv1 gene deletion results in excessive inflammation, exaggerates cardiac hypertrophy, and deteriorates cardiac function after TAC, which may be due to abnormal cardiac remodeling and decreased CGRP in the absence of TRPV1.


Assuntos
Cardiomegalia/genética , Cardiomegalia/patologia , Deleção de Genes , Canais de Cátion TRPV/genética , Animais , Aorta/patologia , Peptídeo Relacionado com Gene de Calcitonina/sangue , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Colágeno/metabolismo , Constrição Patológica , Fibrose , Interleucina-6/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Tamanho do Órgão , Pressão , Fator de Necrose Tumoral alfa/metabolismo , Disfunção Ventricular/diagnóstico por imagem , Disfunção Ventricular/patologia , Disfunção Ventricular/fisiopatologia
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