RESUMO
Despite its well-known antithrombotic properties, the effect of aspirin on blood pressure (BP) and hypertension pathology is unclear. The hugely varying doses used clinically have contributed to this confusion, with high-dose aspirin still commonly used due to concerns about the efficacy of low-dose aspirin. Because prostaglandins have been shown to both promote and inhibit T-cell activation, we also explored the immunomodulatory properties of aspirin in hypertension. Although the common preclinical high dose of 100 mg/kg/d improved vascular dysfunction and cardiac hypertrophy, this effect was accompanied by indices of elevated adaptive immunity, renal T-cell infiltration, renal fibrosis, and BP elevation in stroke-prone spontaneously hypertensive rats and in angiotensin II-induced hypertensive mice. The cardioprotective effects of aspirin were conserved with a lower dose (10 mg/kg/d) while circumventing heightened adaptive immunity and elevated BP. We also show that low-dose aspirin improves renal fibrosis. Differential inhibition of the COX-2 isoform may underlie the disparate effects of the 2 doses. Our results demonstrate the efficacy of low-dose aspirin in treating a vast array of cardiovascular parameters and suggest modulation of adaptive immunity as a novel mechanism underlying adverse cardiovascular profiles associated with COX-2 inhibitors. Clinical studies should identify the dose of aspirin that achieves maximal cardioprotection with a new awareness that higher doses of aspirin could trigger undesired autoimmunity in hypertensive individuals. This work also warrants an evaluation of high-dose aspirin and COX-2 inhibitor therapy in sufferers of inflammatory conditions who are already at increased risk for cardiovascular disease.-Khan, S. I., Shihata, W. A., Andrews, K. L., Lee, M. K. S., Moore, X.-L., Jefferis, A.-M., Vinh, A., Gaspari, T., Dragoljevic, D., Jennings, G. L., Murphy, A. J., Chin-Dusting, J. P. F. Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat.
Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Aspirina/farmacologia , Hipertensão/tratamento farmacológico , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/imunologia , Angiotensina II/farmacologia , Animais , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Cardiomegalia/tratamento farmacológico , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Citocinas/sangue , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Epoprostenol/biossíntese , Hipertensão/induzido quimicamente , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/patologia , Camundongos , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Reação em Cadeia da Polimerase em Tempo Real , Sístole , Linfócitos T/imunologia , Tromboxanos/sangueRESUMO
Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the ß-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.
Assuntos
Aterosclerose/sangue , Aterosclerose/etiologia , Hematopoese , Hipertensão/complicações , Hipertensão/etiologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Aterosclerose/patologia , Bloqueio Nervoso Autônomo , Biomarcadores , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Mielopoese , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-TroncoRESUMO
The essential role of the Y chromosome in male sex determination has largely overshadowed the possibility that it may exert other biologic roles. Here, we show that Y-chromosome lineage is a strong determinant of perivascular and renal T-cell infiltration in the stroke-prone spontaneously hypertensive rat, which, in turn, may influence vascular function and blood pressure (BP). We also show, for the first time to our knowledge, that augmented perivascular T-cell levels can directly instigate vascular dysfunction, and that the production of reactive oxygen species that stimulate cyclo-oxygenase underlies this. We thus provide strong evidence for the consideration of Y-chromosome lineage in the diagnosis and treatment of male hypertension, and point to the modulation of cardiovascular organ T-cell infiltration as a possible mechanism that underpins Y- chromosome regulation of BP.-Khan, S. I., Andrews, K. L., Jackson, K. L., Memon, B., Jefferis, A.-M., Lee, M. K. S., Diep, H., Wei, Z., Drummond, G. R., Head, G. A., Jennings, G. L., Murphy, A. J., Vinh, A., Sampson, A. K., Chin-Dusting, J. P. F. Y-chromosome lineage determines cardiovascular organ T-cell infiltration in the stroke-prone spontaneously hypertensive rat.
Assuntos
Pressão Sanguínea , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Linfócitos T/metabolismo , Cromossomo Y/metabolismo , Animais , Hipertensão/genética , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Transgênicos , Linfócitos T/patologia , Cromossomo Y/genéticaRESUMO
Vascular dysfunction is a hallmark of hypertension and the strongest risk factor to date for coronary artery disease. As Y chromosome lineage has emerged as one of the strongest genetic predictors of cardiovascular disease risk to date, we investigated if Y chromosome lineage modulated this important facet in the stroke-prone spontaneously hypertensive rat (SHRSP) using consomic strains. Here, we show that vascular dysfunction in the SHRSP is attributable to differential cyclooxygenase (COX) activity with nitric oxide (NO) levels playing a less significant role. Measurement of prostacyclin, the most abundant product of COX in the vasculature, confirmed the augmented COX activity in the SHRSP aorta. This was accompanied by functional impairment of the vasodilatory prostacyclin (IP) receptor, while inhibition of the thromboxane (TP) receptor significantly ameliorated vascular dysfunction in the SHRSP, suggesting this is the downstream target responsible for constrictor prostanoid activity. Importantly, Y chromosome lineage was shown to modulate vascular function in the SHRSP through influencing COX activity, prostacyclin levels and IP dysfunction. Vascular dysfunction in the renal and intrarenal arteries was also found to be prostanoid and Y chromosome dependent. Interestingly, despite no apparent differences in agonist-stimulated NO levels, basal NO levels were compromised in the SHRSP aorta, which was also Y chromosome dependent. Thus, in contrast with the widely held view that COX inhibition is deleterious for the vasculature due to inhibition of the vasodilator prostacyclin, we show that COX inhibition abolishes vascular dysfunction in three distinct vascular beds, with IP dysfunction likely being a key mechanism underlying this effect. We also delineate a novel role for Y chromosome lineage in regulating vascular function through modulation of COX and basal NO levels.
Assuntos
Aorta/fisiopatologia , Hipertensão/fisiopatologia , Prostaglandinas/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Cromossomo Y , Acetilcolina/farmacologia , Animais , Aorta/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/genética , Masculino , Óxido Nítrico/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/genética , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Pre-clinical studies have identified nitroxyl (HNO), the reduced congener of nitric oxide (NOâ¢), as a potent vasodilator which is resistant to tolerance development. The present study explores the efficacy of HNO in human blood vessels and describes, for the first time, a vasodilator for humans that is not susceptible to tolerance. Human radial arteries and saphenous veins were obtained from patients undergoing coronary artery graft surgery and mounted in organ baths. Repeated vasodilator responses to the HNO donor Angeli's salt (AS) and NO⢠donor glyceryl trinitrate (GTN) were determined. AS- and GTN-induced concentration-dependent vasorelaxation of both human radial arteries (AS pEC50: 6.5 ± 0.2; -log M) and saphenous veins (pEC50: 6.7 ± 0.1) with similar potency. In human radial arteries, GTN-induced relaxation was reduced by the NO⢠scavenger hydroxocobalamin (HXC; P<0.05) but was unaffected by the HNO scavenger L-cysteine. Alternately, AS was unaffected by HXC but was reduced by L-cysteine (5-fold shift, P<0.05). The sGC (soluble guanylate cyclase) inhibitor ODQ abolished responses to both AS and GTN in arteries and veins (P<0.05). Inhibition of voltage-dependent potassium channels (Kv channels) with 4-AP also significantly reduced responses to AS (pEC50: 5.5) and GTN, suggesting that the relaxation to both redox congeners is cGMP- and Kv channel-dependent. Critically, a concentration-dependent development of tolerance to GTN (1 and 10 µM; P<0.05), but not to AS, was observed in both saphenous veins and radial arteries. Like GTN, the HNO donor AS causes vasorelaxation of human blood vessels via activation of a cGMP-dependent pathway. Unlike GTN, however, it does not develop tolerance in human blood vessels.
Assuntos
Doadores de Óxido Nítrico/farmacologia , Nitritos/farmacologia , Óxidos de Nitrogênio/farmacologia , Nitroglicerina/farmacologia , Artéria Radial/efeitos dos fármacos , Veia Safena/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Guanilato Ciclase/metabolismo , Humanos , Técnicas In Vitro , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Artéria Radial/fisiologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Veia Safena/fisiologia , Guanilil Ciclase SolúvelRESUMO
The hormone, relaxin (RLX), exerts various organ-protective effects independently of etiology. However, its complex two-chain and three disulphide bonded structure is a limitation to its preparation and affordability. Hence, a single chain-derivative of RLX, B7-33, was developed and shown to retain the anti-fibrotic effects of RLX in vitro and in vivo. Here, we determined whether B7-33 could retain the other cardioprotective effects of RLX, and also compared its therapeutic efficacy to the ACE inhibitor, perindopril. Adult male 129sv mice were subjected to isoprenaline (ISO; 25 mg/kg/day, s.c)-induced cardiomyopathy, then s.c-treated with either RLX (0.5 mg/kg/day), B7-33 (0.25 mg/kg/day; equivalent dose corrected for MW) or perindopril (1 mg/kg/day) from days 7-14 post-injury. Control mice received saline instead of ISO. Changes in animal body weight (BW) and systolic blood pressure (SBP) were measured weekly, whilst cardiomyocyte hypertrophy and measures of vascular dysfunction and rarefaction, left ventricular (LV) inflammation and fibrosis were assessed at day 14 post-injury. ISO-injured mice had significantly increased LV inflammation, cardiomyocyte hypertrophy, fibrosis, vascular rarefaction and aortic contractility in the absence of any changes in BW or SBP at day 14 post-injury. Both B7-33 and RLX equivalently reduced LV fibrosis and normalised the ISO-induced LV inflammation and cardiomyocyte hypertrophy, whilst restoring blood vessel density and aortic contractility. Comparatively, perindopril lowered SBP and the ISO-induced LV inflammation and vascular rarefaction, but not fibrosis or hypertrophy. As B7-33 retained the cardioprotective effects of RLX and provided rapid-occurring anti-fibrotic effects compared to perindopril, it could be considered as a cost-effective cardioprotective therapy.
Assuntos
Cardiomiopatias , Rarefação Microvascular , Relaxina , Camundongos , Animais , Masculino , Perindopril/farmacologia , Perindopril/uso terapêutico , Relaxina/farmacologia , Rarefação Microvascular/tratamento farmacológico , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/prevenção & controle , Modelos Teóricos , Inflamação/tratamento farmacológico , Hipertrofia/tratamento farmacológicoRESUMO
The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.
Assuntos
Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Caveolina 1/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea , Cavéolas/metabolismo , Adesão Celular , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Hipertensão/patologia , Rim/patologia , Leucócitos/patologia , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , NF-kappa B/metabolismo , Norepinefrina , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
The consequences of estrogen deficiency on the cardiovascular system have been widely examined in females. The effects of endogenous estrogen deficiency in males are less clear. The aromatase-knockout (ArKO) mouse lacks a functional Cyp19 gene, which encodes aromatase, and is thus incapable of synthesizing endogenous estrogen. In the present study, we examined the effect of lack of endogenous estrogens on vascular function in aortic rings isolated from male ArKO mice and compared these effects to rings from wild-type (WT) littermates. Full concentration-response curves to norepinephrine, acetylcholine, isoprenaline, and sodium nitroprusside were obtained in the absence and presence of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine in aortic segments set up in isometric myographs. Responses to noradrenaline were not different in aorta from ArKO compared with WT mice. Both Nomega-nitro-L-arginine and endothelium denudation significantly shifted the noradrenaline concentration-response curve to the left; however, this shift was not different in ArKO compared with WT. Responses to the endothelium-dependent vasodilator acetylcholine were significantly blunted in aortic rings from ArKO mice (Emax, 58.2+/-0.9% and 34.0+/-0.5% in wild-type and ArKO, respectively; P<0.05), whereas responses to the endothelium-independent agonist sodium nitroprusside and to the partial endothelium-dependent agonist isoprenaline were not affected. These findings suggest that endogenous estrogen facilitate vasorelaxation in males. This may be via modulating endothelial function rather than vascular smooth muscle cell responsiveness.
Assuntos
Acetilcolina/farmacologia , Aorta/efeitos dos fármacos , Aromatase/metabolismo , Estrogênios/metabolismo , Óxido Nítrico/metabolismo , Animais , Aorta/metabolismo , Aorta/fisiologia , Aromatase/genética , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Genótipo , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologiaRESUMO
Microvascular complications are now recognized to play a major role in diabetic complications, and understanding the mechanisms is critical. Endothelial dysfunction occurs early in the course of the development of complications; the precise mechanisms remain poorly understood. Mitochondrial dysfunction may occur in a diabetic rat heart and may act as a source of the oxidative stress. However, the role of endothelial cell-specific mitochondrial dysfunction in diabetic vascular complications is poorly studied. Here, we studied the role of diabetes-induced abnormal endothelial mitochondrial function and the resultant endothelial dysfunction. Understanding the role of endothelial mitochondrial dysfunction in diabetic vasculature is critical in order to develop new therapies. We demonstrate that hyperglycaemia leads to mitochondrial dysfunction in microvascular endothelial cells, and that mitochondrial inhibition induces endothelial dysfunction. Additionally, we show that resveratrol acts as a protective agent; resveratrol-mediated mitochondrial protection may be used to prevent long-term diabetic cardiovascular complications.
Assuntos
Doença da Artéria Coronariana/prevenção & controle , Vasos Coronários/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Células Endoteliais/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Glicemia/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/fisiopatologia , Células Endoteliais/metabolismo , Humanos , Preparação de Coração Isolado , Masculino , Microcirculação/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/fisiopatologia , Mitocôndrias/metabolismo , Contração Miocárdica/efeitos dos fármacos , Ratos Sprague-Dawley , Resveratrol , Fatores de Tempo , Vasodilatação/efeitos dos fármacosRESUMO
Soluble P-selectin (sP-selectin), a biomarker of inflammatory related pathologies including cardiovascular and peripheral vascular diseases, also has pro-atherosclerotic effects including the ability to increase leukocyte recruitment and modulate thrombotic responses in vivo. The current study explores its role in progressing atherosclerotic plaque disease. Apoe-/- mice placed on a high fat diet (HFD) were given daily injections of recombinant dimeric murine P-selectin (22.5 µg/kg/day) for 8 or 16 weeks. Saline or sE-selectin injections were used as negative controls. In order to assess the role of sP-selectin on atherothrombosis an experimental plaque remodelling murine model, with sm22α-hDTR Apoe-/- mice on a HFD in conjunction with delivery of diphtheria toxin to induce targeted vascular smooth muscle apoptosis, was used. These mice were similarly given daily injections of sP-selectin for 8 or 16 weeks. While plaque mass and aortic lipid content did not change with sP-selectin treatment in Apoe-/- or SM22α-hDTR Apoe-/- mice on HFD, increased plasma MCP-1 and a higher plaque CD45 content in Apoe-/- HFD mice was observed. As well, a significant shift towards a more unstable plaque phenotype in the SM22α-hDTR Apoe-/- HFD mice, with increased macrophage accumulation and lower collagen content, leading to a lower plaque stability index, was observed. These results demonstrate that chronically raised sP-selectin favours progression of an unstable atherosclerotic plaque phenotype.
Assuntos
Gorduras na Dieta/efeitos adversos , Macrófagos/metabolismo , Selectina-P/sangue , Placa Aterosclerótica/metabolismo , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Knockout , Selectina-P/genética , Placa Aterosclerótica/induzido quimicamente , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologiaRESUMO
Hyperinsulinemia is a risk factor for hypertension and arteriosclerosis. The mechanism by which it contributes to disease progression is not known. The present study examines the effects of insulin on endothelium-derived relaxing factors. Segments of rat mesenteric arterioles and aorta were set up for isometric recordings. The effect of insulin (1 mU/mL) on acetylcholine responses was examined with and without nitro-L-arginine, indomethacin, KCl (40 mmol/L), and apamin+charybdotoxin. Incubation with insulin (maximum response to acetylcholine 90.9+/-8.7% versus 90.7+/-4.5% for before versus after insulin, respectively), nitro-L-arginine, indomethacin, or high K(+) alone had no effect on these responses in mesenteric arterioles. Apamin+charybdotoxin significantly blunted responses to acetylcholine. When coincubated with nitro-L-arginine but not with indomethacin or high K(+), insulin blunted the maximum response to acetylcholine (from 84.8+/-8.2% to 40.7+/-10.2% for before versus after insulin, respectively; P<0.01). When coincubated with apamin+charybdotoxin, insulin had no further effect. Coadministration of indomethacin with nitro-L-arginine had no greater effect than did nitro-L-arginine alone. The addition of insulin, together with nitro-L-arginine and indomethacin, significantly decreased the maximal response to acetylcholine from 96.6+/-5.3% to 52.9+/-10.8% (P<0.01). In the aorta, nitro-L-arginine abolished acetylcholine responses. Coadministration with insulin had no further effect. We conclude that insulin attenuates acetylcholine responses mediated by endothelium-derived hyperpolarizing factor in small but not large arteries. This effect of insulin is apparent only when NO is blocked and may be important in the development of hypertension or arteriosclerosis when reduced NO function has been reported.