Treatment of Spontaneously Hypertensive Rats With Rosiglitazone and/or Enalapril Restores Balance Between Vasodilator and Vasoconstrictor Actions of Insulin With Simultaneous Improvement in Hypertension and Insulin Resistance

Potenza, Maria Assunta; Marasciulo, Flora L.; Tarquinio, Mariela; Quon, Michael J.; Montagnani, Monica

doi:10.2337/db06-0667

Cited by 80 publications

(63 citation statements)

References 68 publications

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“…The magnitude of vasodilation in response to EGCG that we observed in MVB from WKY rats is comparable with that observed with EGCG treatment of MVB from SHR rats (43). By contrast, insulin-resistant, hypertensive SHR rats have impaired vasodilator responses to insulin when compared with normotensive WKY rats without insulin resistance (13,44). Taken together with the observation that signaling pathways regulating vasodilator actions of EGCG are not completely overlapping with those of insulin, these results raise the possibility that vasodilator actions of EGCG may have beneficial effects on endothelial dysfunction related to insulin resistance.…”

Section: Discussionsupporting

confidence: 48%

Epigallocatechin Gallate, a Green Tea Polyphenol, Mediates NO-dependent Vasodilation Using Signaling Pathways in Vascular Endothelium Requiring Reactive Oxygen Species and Fyn

Kim

Formoso

et al. 2007

Journal of Biological Chemistry

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209

138

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Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, mimics metabolic actions of insulin to inhibit gluconeogenesis in hepatocytes. Because signaling pathways regulating metabolic and vasodilator actions of insulin are shared in common, we hypothesized that EGCG may also have vasodilator actions to stimulate production of nitric oxide (NO) from endothelial cells.

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Section: Discussionsupporting

confidence: 48%

Epigallocatechin Gallate, a Green Tea Polyphenol, Mediates NO-dependent Vasodilation Using Signaling Pathways in Vascular Endothelium Requiring Reactive Oxygen Species and Fyn

Kim

Formoso

et al. 2007

Journal of Biological Chemistry

Self Cite

209

138

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“…It is reported that the decreased endothelin-1 level and amelioration of endothelial function are associated with the effect of rosiglitazone on blood pressure (28). However, due to the lack of direct manipulation of PPAR-␥ expression in vivo in the present study, the exact role of PPAR-␥ in rosiglitazone-mediated SBP regulation is still not clarified.…”

Section: Discussioncontrasting

confidence: 39%

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Zhang

Xie

Wang

et al. 2010

Journal of Biological Chemistry

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The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-␥ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-␥ expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, ␣-smooth muscle actin (␣-SMA) and smooth muscle 22␣ (SM22␣), and enhanced proliferation and migration. PPAR-␥ overexpression rescued the expression of ␣-SMA and SM22␣, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-␥ silencing exerted the opposite effect. Activating PPAR-␥ using rosiglitazone in vivo up-regulated aortic ␣-SMA and SM22␣ expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-␥ inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-␥ silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-␥ overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-␥ inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-␥ expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for hypertension-related vascular disorders.Hypertension and hypertension-induced vascular remodeling underlie numerous cardiovascular disorders. Activated vascular smooth muscle cells (VSMCs) 2 are essential contributors to this vascular remodeling (1). Unlike other muscle cells, VSMCs do not terminally differentiate. They can switch from a differentiated phenotype (also known as contractile or quiescent phenotype) to a dedifferentiated phenotype (also known as synthetic or activated phenotype) in response to vascular injury. In this process, VSMCs regain their proliferative and migratory capacities, secrete matrix proteins, and down-regulate smooth muscle contractile proteins, such as ␣-smooth muscle actin (␣-SMA), smooth muscle 22␣ (SM22␣), smooth muscle myosin heavy chain, and calponin (2). Although this phenotypic modulation is undoubtedly required for vascular repair, inappropriate modulation is associated with increased vascular resistance and aggravates vascular injury. However, despite intensive research efforts, the precise mechanisms underlying VSMC phenotypic modula...

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“…38 Finally, in SHR as well as in patients with essential hypertension endothelial function is impaired and may contribute to reduced vessel regeneration in this setting. [15][16][17] In addition, AT1R blocker and ACE inhibitor have been shown to ameliorate vascular function in SHR, 39,40 suggesting that restoration of endothelium function may participate at least in part to the beneficial effects of AT1R blocker and ACE inhibitor in hypertension.…”

Section: Discussionmentioning

confidence: 99%

Hypertension Impairs Postnatal Vasculogenesis

et al. 2008

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Key Words: hypertension Ⅲ angiogenesis Ⅲ progenitor cells Ⅲ angiotensin converting enzyme Ⅲ angiotensin type I receptor T he revascularization process, including vasculogenesis, angiogenesis, and collateral growth, characterizes tissue repair and remodeling occurring in acute and chronic ischemic vascular diseases. In particular, postnatal vasculogenesis referred to the homing and differentiation of circulating progenitor cells from bone marrow or non-bone marrow origins 1 into endothelial cells within sites of active neovascularization. In addition, circulating progenitor cells may deliver angiogenic growth factors to pathological tissues and contribute to neovascularization and tissue/vessel remodeling by paracrine effects. 2,3 In most clinical settings, however, these natural adaptive responses to a compromised perfusion are insufficient to block the progression of ischemic diseases. Hence, certain cardiovascular risk factors including diabetes, aging, and hypercholesterolemia adversely affect postnatal vasculogenesis and revascularization in animals models of limb ischemia. 4 -7 In support of this view, patients with type I and II diabetes displayed a reduction in endothelial progenitor cell (EPC) number and angiogenicity. 8,9 In most forms of clinical and experimental hypertension, increased arterial blood pressure is associated with microvascular rarefaction and increased peripheral vascular resistances. 10 Similarly, postischemic reparative neovascularization is impaired in spontaneously hypertensive rats (SHR) as a function of progression of the hypertensive disease. 11,12 Several molecular and cellular mechanisms may be involved in the hypertension-induced impairment in vessel growth. First, the angiogenic capacity of serum derived from SHR was less than that from normotensive animals in a chick embryo chorio-allantoic membrane model. 13 Protein levels of key proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor are also reduced in hypertensive animals. 11,14 Second, previous obser-

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Treatment of Spontaneously Hypertensive Rats With Rosiglitazone and/or Enalapril Restores Balance Between Vasodilator and Vasoconstrictor Actions of Insulin With Simultaneous Improvement in Hypertension and Insulin Resistance

Cited by 80 publications

References 68 publications

Epigallocatechin Gallate, a Green Tea Polyphenol, Mediates NO-dependent Vasodilation Using Signaling Pathways in Vascular Endothelium Requiring Reactive Oxygen Species and Fyn

Epigallocatechin Gallate, a Green Tea Polyphenol, Mediates NO-dependent Vasodilation Using Signaling Pathways in Vascular Endothelium Requiring Reactive Oxygen Species and Fyn

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

Hypertension Impairs Postnatal Vasculogenesis

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