Propranolol treatment lowers blood pressure, reduces vascular inflammatory markers and improves endothelial function in obese mice

Franco, Nathalia da Silva; Lubaczeuski, Camila; Guizoni, Daniele M.; Victório, Jamaira A.; Santos-Silva, Junia Carolina; Brum, Patrícia Chakur; Carneiro, Everardo M.; Davel, Ana Paula

doi:10.1016/j.phrs.2017.05.018

Cited by 17 publications

(8 citation statements)

References 58 publications

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“…However, other cardiometabolic parameters such as plasma insulin and glucose as well as systolic arterial blood pressure were not significantly elevated in either of the HFD groups compared to groups fed the normal diet. This is in contrast with a previous study in mice on a 54% kcal fat diet for only 8 weeks (da Silva Franco et al, 2017 ). In terms of plasma glucose and insulin, most studies report a rise induced by HFD, even after only 4 weeks of feeding (Guilford et al, 2017 ), but others have found no change after 6 weeks (60% kcal of fat diet; Zhang et al, 2017 ).…”

Section: Discussioncontrasting

confidence: 93%

High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion

et al. 2018

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Background and aim: Perivascular adipose tissue (PVAT) positively regulates vascular function through production of factors such as adiponectin but this effect is attenuated in obesity. The enzyme AMP-activated protein kinase (AMPK) is present in PVAT and is implicated in mediating the vascular effects of adiponectin. In this study, we investigated the effect of an obesogenic high fat diet (HFD) on aortic PVAT and whether any changes involved AMPK.Methods: Wild type Sv129 (WT) and AMPKα1 knockout (KO) mice aged 8 weeks were fed normal diet (ND) or HFD (42% kcal fat) for 12 weeks. Adiponectin production by PVAT was assessed by ELISA and AMPK expression studied using immunoblotting. Macrophages in PVAT were identified using immunohistochemistry and markers of M1 and M2 macrophage subtypes evaluated using real time-qPCR. Vascular responses were measured in endothelium-denuded aortic rings with or without attached PVAT. Carotid wire injury was performed and PVAT inflammation studied 7 days later.Key results: Aortic PVAT from KO and WT mice was morphologically indistinct but KO PVAT had more infiltrating macrophages. HFD caused an increased infiltration of macrophages in WT mice with increased expression of the M1 macrophage markers Nos2 and Il1b and the M2 marker Chil3. In WT mice, HFD reduced the anticontractile effect of PVAT as well as reducing adiponectin secretion and AMPK phosphorylation. PVAT from KO mice on ND had significantly reduced adiponectin secretion and no anticontractile effect and feeding HFD did not alter this. Wire injury induced macrophage infiltration of PVAT but did not cause further infiltration in KO mice.Conclusions: High-fat diet causes an inflammatory infiltrate, reduced AMPK phosphorylation and attenuates the anticontractile effect of murine aortic PVAT. Mice lacking AMPKα1 phenocopy many of the changes in wild-type aortic PVAT after HFD, suggesting that AMPK may protect the vessel against deleterious changes in response to HFD.

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Section: Discussioncontrasting

confidence: 93%

High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion

et al. 2018

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“…We found no differences in ROS generation, total eNOS expression, or the degree of eNOS serine 1177 phosphorylation, an important posttranslational modification that enhances eNOS activity. Although increased vascular ROS generation has be found in response to obesity, dyslipidemia, and metabolic syndrome,46 in early stages of obesity, vascular oxidative stress might not be present 47, 48. We cannot exclude the possibility that risk factors modify eNOS activity and NO bioavailability through modulation of a different eNOS phosphorylation site other than serine 1177, such as the inhibitory threonine 495 phosphorylation site or others.…”

Section: Discussionmentioning

confidence: 94%

“…Although increased vascular ROS generation has be found in response to obesity, dyslipidemia, and metabolic syndrome, 46 in early stages of obesity, vascular oxidative stress might not be present. 47,48 We cannot exclude the possibility that risk factors modify eNOS activity and NO bioavailability through modulation of a different eNOS phosphorylation site other than serine 1177, such as the inhibitory threonine 495 phosphorylation site or others. In obese males only, the impairment in NO was associated with increased EDHmediated relaxation and a specific increase in mesenteric protein expression of the endothelial SK3 potassium channel.…”

Section: Controlmentioning

confidence: 99%

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Davel

Lü

Moss

et al. 2018

JAHA

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BackgroundThe incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (MR) activation, we tested the hypothesis that MR in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors.Methods and ResultsMale and female endothelial cell–specific MR knockout mice and MR‐intact littermates were randomized to high‐fat‐diet–induced obesity or obesity with hyperlipidemia induced by adeno‐associated virus–based vector targeting transfer of the mutant stable form (DY mutation) of the human PCSK9 (proprotein convertase subtilisin/kexin type 9) gene and compared with control diet. Female but not male mice were sensitive to obesity‐induced endothelial dysfunction, whereas endothelial function was impaired in obese hyperlipidemic males and females. In males, obesity or hyperlipidemia decreased the nitric oxide component of vasodilation without altering superoxide production or endothelial nitric oxide synthase expression or phosphorylation. Decreased nitric oxide content in obese males was overcome by enhanced endothelium‐derived hyperpolarization–mediated relaxation along with increased SK3 expression. Conversely, in females, endothelium‐derived hyperpolarization was significantly impaired by obesity with lower IK1 expression and by hyperlipidemia with lower IK1 and SK3 expression, loss of H2O2‐mediated vasodilation, and increased superoxide production. Endothelial cell–MR deletion prevented endothelial dysfunction induced by risk factors only in females. Rather than restoring endothelium‐derived hyperpolarization in females, endothelial cell–MR deletion enhanced nitric oxide and prevented hyperlipidemia‐induced oxidative stress.ConclusionsThese data reveal distinct mechanisms driving resistance vessel dysfunction in males versus females and suggest that personalized treatments are needed to prevent the progression of vascular disease in the setting of obesity, depending on both the sex and the metabolic profile of each patient.

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“…Insulin enhances the expression and activity of eNOS in endothelial cells by upregulating the PI3K/Akt pathway, which induced endothelium-dependent relaxation (Montagnani et al, 2002 ; Potenza et al, 2009 ). However, hyperinsulinemia and insulin resistance favor the insulin-dependent activation of MAP-kinases (MAPK), which is associated with the elevated expression of proinflammatory and atherogenic factors (Eringa et al, 2004 ; Cersosimo et al, 2012 ; da Silva Franco et al, 2017 ). The presence of PVAT prevented the reduced insulin-induced relaxation in aorta of LDLr-KO mice.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Perivascular Adipose Tissue in Endothelial Dysfunction and Insulin-Induced Vasodilatation of Hypercholesterolemic LDL Receptor-Deficient Mice

et al. 2018

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Background: Endothelial dysfunction plays a pivotal role in the initiation of atherosclerosis. Vascular insulin resistance might contribute to a reduction in endothelial nitric oxide (NO) production, leading to impaired endothelium-dependent relaxation in cardiometabolic diseases. Because perivascular adipose tissue (PVAT) controls endothelial function and NO bioavailability, we hypothesized a role for this fat deposit in the vascular complications associated with the initial stages of atherosclerosis. Therefore, we investigated the potential involvement of PVAT in the early endothelial dysfunction in hypercholesterolemic LDL receptor knockout mice (LDLr-KO).Methods: Thoracic aortas with and without PVAT were isolated from 4-month-old C57BL/6J (WT) and LDLr-KO mice. The contribution of PVAT to relaxation responses to acetylcholine, insulin, and sodium nitroprusside was investigated. Western blotting was used to examine endothelial NO synthase (eNOS) and adiponectin expression, as well the insulin signaling pathway in aortic PVAT.Results: PVAT-free aortas of LDLr-KO mice exhibited impaired acetylcholine- and insulin-induced relaxation compared with those of WT mice. Both vasodilatory responses were restored by the presence of PVAT in LDLr-KO mice, associated with enhanced acetylcholine-induced NO levels. PVAT did not change vasodilatory responses to acetylcholine and insulin in WT mice, while vascular relaxation evoked by the NO donor sodium nitroprusside was not modified by either genotype or PVAT. The expression of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), AKT, ERK1/2, phosphorylation of AKT (Ser473) and ERK1/2 (Thr202/Tyr204), and adiponectin was similar in the PVAT of WT and LDLr-KO mice, suggesting no changes in PVAT insulin signaling. However, eNOS expression was enhanced in the PVAT of LDLr-KO mice, while eNOS expression was less abundant in PVAT-free aortas.Conclusion: These results suggest that elevated eNOS-derived NO production in aortic PVAT might be a compensatory mechanism for the endothelial dysfunction and impaired vasodilator action of insulin in hypercholesterolemic LDLr-deficient mice. This protective effect may limit the progression of atherosclerosis in genetic hypercholesterolemia in the absence of an atherogenic diet.

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Propranolol treatment lowers blood pressure, reduces vascular inflammatory markers and improves endothelial function in obese mice

Cited by 17 publications

References 58 publications

High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion

High Fat Diet Attenuates the Anticontractile Activity of Aortic PVAT via a Mechanism Involving AMPK and Reduced Adiponectin Secretion

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

Protective Role of Perivascular Adipose Tissue in Endothelial Dysfunction and Insulin-Induced Vasodilatation of Hypercholesterolemic LDL Receptor-Deficient Mice

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