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Ernesto L Schiffrin

Publications and source records attributed to Ernesto L Schiffrin.

At least 19 recordsLinked to original sources
PubMed2006

Angiotensin receptor blocker added to previous antihypertensive agents on arteries of diabetic hypertensive patients.

Lowering elevated blood pressure (BP) in diabetic hypertensive individuals decreases cardiovascular events. We questioned whether remodeling of resistance arteries from hypertensive diabetic patients would improve after 1 year of tight BP control with addition of either the angiotensin receptor blocker (ARB) valsartan or the beta-blocker (BB) atenolol to previous therapy, which included angiotensin-converting enzyme inhibitors (ACEIs) and/or calcium channel blockers. Twenty-eight hypertensive type 2 diabetic patients treated with oral hypoglycemic and antihypertensive agents (not receiving ARBs or BBs) were randomly assigned to double-blind treatment for 1 year with valsartan (80 to 160 mg) or atenolol (50 to 100 mg) daily, added to previous therapy. Resistance arteries dissected from gluteal subcutaneous tissues were assessed on a pressurized myograph. After 1 year of treatment, systolic and diastolic BP and glycemia were equally well controlled in the valsartan and atenolol groups. Endothelium-dependent and independent relaxation did not change in the treated groups. After 1 year of treatment, resistance artery media:lumen ratio decreased in the valsartan group (7.9+/-0.5% after versus 9.8+/-0.6% before; P < 0.05) but not in the atenolol-treated group (9.9+/-0.9% versus 10.6+/-1%; P value not significant). Artery walls from atenolol-treated patients became stiffer, with no change in the valsartan-treated patients. In conclusion, similar intensive BP control for 1 year with valsartan was associated with improved structure of resistance arteries in diabetic hypertensive patients, whereas vessels from atenolol-treated patients exhibited unchanged remodeling and a stiffer wall. The addition of ARBs but not BBs to antihypertensive medications that may include angiotensin-converting enzyme inhibitors and/or calcium channel blockers results in an improvement in resistance artery remodeling in diabetic hypertensive patients.

Adult↗
PubMed2006

Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications.

Peroxisome proliferator-activated receptors (PPAR)alpha, gamma and beta/delta belong to the nuclear receptor family of ligand-activated transcription factors. PPARs heterodimerize with the retinoid X receptor (RXR) and then act as transcription factors to modulate the function of many target genes. PPARalpha, gamma and beta/delta subtypes have significant differences in their ligand and gene specificities. PPARalpha is activated by polyunsaturated fatty acids and by fibrate drugs (fenofibrate and gemfibrozil) and controls expression of genes involved in lipid metabolism. PPARgamma is activated by fatty acid derivatives, such as hydroxyoctadecadienoic acid (HODEs), prostaglandin derivatives, such as 15-deoxy-Delta12,14-prostaglandin J2, and thiazolidinedione (glitazone) drugs, such as pioglitazone and rosiglitazone. PPARgamma is a key regulator of glucose homeostasis and adipogenesis. PPARbeta/delta ligands include polyunsaturated fatty acids, prostaglandins and synthetic compounds and stimulate fatty acid oxidation. All PPARs are expressed in vascular cells where they exert antiatherogenic, anti-inflammatory and vasculoprotective actions. Activators of PPARalpha (fibrates) and PPARgamma (thiazolidinediones or glitazones) antagonize angiotensin II effects in vivo and in vitro and have cardiovascular antioxidant and anti-inflammatory actions. PPAR agonists slightly reduce blood pressure are cardio-protective and correct vascular structure and endothelial dysfunction in experimental models of hypertension. Because of these beneficial effects, activators of PPARs may have therapeutic potential in the prevention of cardiovascular disease beyond their actions on carbohydrate and lipid metabolism. The present chapter focuses on the role of PPARs in vascular biology and discusses the clinical implications of using PPAR agonists in the management of vascular disease.

Animals↗
PubMed2006

The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part I--Blood pressure measurement, diagnosis and assessment of risk.

OBJECTIVE: To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with high blood pressure. OPTIONS AND OUTCOMES: For persons in whom a high blood pressure value is recorded, a diagnosis of hypertension is dependent on the appropriate measurement of blood pressure, the level of the blood pressure elevation, the approach used to monitor blood pressure (office, ambulatory or home/self), and the duration of follow-up. In addition, the presence of cardiovascular risk factors and target organ damage should be assessed to determine the urgency, intensity and type of treatment. For persons diagnosed as having hypertension, estimating the overall risk of adverse cardiovascular outcomes requires an assessment for other vascular risk factors and hypertensive target organ damage. EVIDENCE: MEDLINE searches were conducted from November 2004 to October 2005 to update the 2005 recommendations. Reference lists were scanned, experts were polled, and the personal files of the authors and subgroup members were used to identify other studies. Identified articles were reviewed and appraised using prespecified levels of evidence by content and methodological experts. As per previous years, the authors only included studies that had been published in the peer-reviewed literature and did not include evidence from abstracts, conference presentations or unpublished personal communications. RECOMMENDATIONS: The present document contains recommendations for blood pressure measurement, diagnosis of hypertension, and assessment of cardiovascular risk for adults with high blood pressure. These include the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, assessment of overall cardiovascular risk, routine and optional laboratory testing, assessment for renovascular and endocrine causes, home and ambulatory blood pressure monitoring, and the role of echocardiography for those with hypertension. Key features of the 2006 recommendations include continued emphasis on an expedited diagnosis of hypertension, an in-depth review of the role of global risk assessment in hypertension therapy, and the use of home/self blood pressure monitoring for patients with masked hypertension (subjects with hypertension who have a blood pressure that is normal in clinic but elevated on home/self measurement). VALIDATION: All recommendations were graded according to the strength of the evidence and were voted on by the 45 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported herein received at least 95% consensus. These guidelines will continue to be updated annually.

Advisory Committees↗
PubMed2006

The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part II - Therapy.

OBJECTIVE: To provide updated, evidence-based recommendations for the management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence from randomized, controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. For lifestyle interventions, blood pressure (BP) lowering was accepted as a primary outcome given the lack of long-term morbidity/mortality data in this field. For treatment of patients with kidney disease, the development of proteinuria or worsening of kidney function was also accepted as a clinically relevant primary outcome. EVIDENCE: MEDLINE searches were conducted from November 2004 to October 2005 to update the 2005 recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: Lifestyle modifications to prevent and/or treat hypertension include the following: perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week in men or nine standard drinks per week in women; follow a diet that is reduced in saturated fat and cholesterol and that emphasizes fruits, vegetables and low-fat dairy products; restrict salt intake; and consider stress management in selected individuals. Treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and comorbid conditions. BP should be lowered to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease (regardless of the degree of proteinuria). Most adults with hypertension require more than one agent to achieve these target BPs. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic hypertension with or without systolic hypertension include beta-blockers (in those younger than 60 years), angiotensin-converting enzyme (ACE) inhibitors (in nonblack patients), long-acting calcium channel blockers or angiotensin receptor antagonists. Other agents for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine calcium channel blockers or angiotensin receptor antagonists. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with diabetes mellitus, ACE inhibitors or angiotensin receptor antagonists (or in patients without albuminuria, thiazides or dihydropyridine calcium channel blockers) are appropriate first-line therapies; and in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended. All hypertensive patients should have their fasting lipids screened, and those with dyslipidemia should be treated using the thresholds, targets and agents recommended by the Canadian Hypertension Education Program Working Group on the management of dyslipidemia and the prevention of cardiovascular disease. Selected patients with hypertension, but without dyslipidemia, should also receive statin therapy and/or acetylsalicylic acid therapy. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the 45 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Advisory Committees↗
PubMed2006

Inhibition of the renin angiotensin system: implications for the endothelium.

The endothelium is critically involved in modulating vascular tone through the release of vasodilator (mainly nitric oxide; NO) and vasoconstrictor agents. Under normal conditions the endothelium induces NO-mediated vasodilation, and opposes cell adhesion and thrombosis. Angiotensin II-induced generation of reactive oxygen species plays a key role in the pathophysiology of endothelial dysfunction by reducing NO bioavailability. Endothelial dysfunction is associated with several pathologic conditions, including hypertension and diabetes, and is characterized by altered vascular tone, inflammation, and thrombosis in the vascular wall. Inhibition of the renin-angiotensin-aldosterone system has induced beneficial effects on endothelial function in animals and humans. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists have improved endothelial function in hypertension and diabetes, slowed the progression of atherosclerosis, and reduced the risk associated with cardiovascular disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Increased systemic inflammation and oxidative stress in patients with worsening congestive heart failure: improvement after short-term inotropic support.

In the present study, we evaluated circulating pro-inflammatory mediators and markers of oxidative stress in patients with decompensated CHF (congestive heart failure) and assessed whether clinical recompensation by short-term inotropic therapy influences these parameters. Patients with worsening CHF (n=29, aged 61.9+/-2.7 years), NYHA (New York Heart Association) class III-IV, and left ventricular ejection fraction of 23.7+/-1.8% were studied. Controls comprised age-matched healthy volunteers (n=15; 54.1+/-3.2 years). Plasma levels of cytokines [IL (interleukin)-6 and IL-18], chemokines [MCP-1 (monocyte chemotactic protein-1)], adhesion molecules [sICAM (soluble intercellular adhesion molecule), sE-selectin (soluble E-selectin)], systemic markers of oxidation [TBARS (thiobarbituric acid-reactive substances), 8-isoprostaglandin F(2alpha) and nitrotyrosine] and hs-CRP (high-sensitivity C-reactive protein) were measured by ELISA and colorimetric assays at admission and 30 days following 72-h milrinone (n=15) or dobutamine (n=14) infusion. Plasma IL-6, IL-18, sICAM, E-selectin, hs-CRP and oxidative markers were significantly higher in patients on admission before inotropic treatment compared with controls (P<0.05). Short-term inotropic support improved clinical status as assessed by NYHA classification and by the 6-min walk test and significantly decreased plasma levels of IL-6, IL-18, sICAM, hs-CRP and markers of oxidation (P<0.05) at 30 days. The effects of milrinone and dobutamine were similar. In conclusion, our results demonstrate that patients with decompensated CHF have marked systemic inflammation and increased production of oxygen free radicals. Short-term inotropic support improves functional status and reduces indices of inflammation and oxidative stress in patients with decompensated CHF.

Biomarkers↗
PubMed2006

Angiotensin II induces vascular dysfunction without exacerbating blood pressure elevation in a mouse model of menopause-associated hypertension.

BACKGROUND: Follitropin-receptor knockout (FORKO) mice are estrogen-deficient, hyperandrogenic and exhibit features of menopause and elevated blood pressure (BP). Because the renin-angiotensin system has been implicated in menopause-associated hypertension, we questioned whether angiotensin II (Ang II) challenge would further increase BP in FORKO mice and whether this is associated with cardiovascular remodeling and inflammation. RESULTS: Ang II (400 ng/kg per min) increased BP, assessed by radiotelemetry, similarly in female FORKO and wild-type (WT) mice. Acetylcholine-induced vasodilation was attenuated and Ang II-induced contraction was enhanced in FORKO mice (P < 0.05). This was associated with increased expression of vascular Ang type 1 receptors (AT1R) and estrogen receptor alpha (ERalpha). Vascular structure (media/lumen ratio) was similar in both groups. Abundance of gp91, nitrotyrosine formation and superoxide production, indices of inflammation and cardiac collagen content were increased in Ang II-treated FORKO compared to Ang II-treated WT mice (P < 0.05). CONCLUSIONS: Thus, in FORKO mice Ang II exacerbates endothelial dysfunction, augments contractility, increases oxidative stress, and promotes cardiac fibrosis without worsening vascular remodeling or BP elevation compared to Ang II-treated WT controls. Our findings suggest that in FORKO mice Ang II may be more important in influencing vascular tone and endothelial function, possibly through oxidative stress and altered ERalpha signaling, than in arterial remodeling and BP elevation.

Angiotensin II↗
PubMed2006

Angiotensin II/AT2 receptor-induced vasodilation in stroke-prone spontaneously hypertensive rats involves nitric oxide and cGMP-dependent protein kinase.

BACKGROUND: Angiotensin II (Ang II) induces vasodilation, in part, through angiotensin type 2 receptor (AT2R)-induced actions in conditions associated with angiotensin type 1 receptor (AT1R) blockade and AT2R upregulation. Ang II/AT2R-induced vasodilation involves nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-dependent processes. We previously demonstrated that AT2R-mediated effects involve inhibition of the RhoA/Rho kinase pathway. However, molecular mechanisms underlying this phenomenon are unknown. AIMS: In the present in-vivo study we tested the hypothesis that AT2R-elicited vasodilation is associated with nitric oxide synthase (NOS) activation and NO production, and that a cGMP-dependent protein kinase (cGKI), which inactivates RhoA, is upregulated when stroke-prone spontaneously hypertensive rats (SHRSP) are treated with AT1R blockers. METHODS: SHRSP and Wistar-Kyoto (WKY) rats were treated with the AT1R blocker valsartan for 14 days. Dilatory responses to Ang II with or without the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) were performed in norepinephrine-precontracted vessels in the presence of valsartan. Expression of AT2R, endothelial NOS (eNOS) and cGKI was assessed by immunoblotting. NO bioavailability and NAD(P)H oxidase activity were evaluated by chemiluminescence. RESULTS: Ang II elicited vasodilation in valsartan-treated SHRSP. L-NAME inhibited this effect, indicating a role for NO. eNOS expression and NO concentration were increased twofold by valsartan, only in SHRSP. Expression of cGKI was reduced in SHRSP and restored after valsartan treatment. NAD(P)H oxidase activity was approximately threefold higher in SHRSP versus WKY (P < 0.05) and reduced by valsartan. CONCLUSIONS: Ang II, via AT2R, facilitates vasodilation through NOS/NO-mediated pathways and upregulation [corrected] of CGK1 [corrected] after chronic AT1R antagonism. These effects may contribute in part to beneficial actions of AT1R blockers in the treatment of hypertension.

Angiotensin Receptor Antagonists↗
PubMed2006

Inflammation in hypertension.

PURPOSE OF REVIEW: In this review we summarize the recent evidence that highlights the involvement of low-grade inflammation in the development and pathophysiology of hypertension. RECENT FINDINGS: Essential hypertension is characterized by increased peripheral vascular resistance to blood flow, due in large part to vascular remodeling. Vascular changes in hypertension are associated with mechanical and humoral factors that modulate signaling events, resulting in abnormal function, media growth, extracellular matrix deposition and inflammation. Recent evidence suggests that inflammation is present in the vasculature in animal models of hypertension. Inflammatory markers, such as C-reactive protein, are associated with vascular lesions in humans, and are predictive of cardiovascular outcome. In animal and human studies, pro-inflammatory components of the renin-angiotensin-aldosterone system have been demonstrated in large conduit and small arteries in the kidney and heart. Peroxisome proliferator-activated receptor activators are drugs with metabolic properties that have been demonstrated to exert anti-inflammatory effects on the vasculature, and there is now evidence that these actions may be protective for blood vessels. SUMMARY: Inflammatory processes are important participants in the pathophysiology of hypertension and cardiovascular disease. The identification of the mechanisms leading to the activation of inflammation should contribute to the development of specific therapeutic approaches to apply in hypertension and its complications.

C-Reactive Protein↗
PubMed2006

The protective effects of angiotensin II blockade with olmesartan medoxomil on resistance vessel remodeling (The VIOS study): rationale and baseline characteristics.

BACKGROUND: The VIOS (Vascular Improvement with Olmesartan medoxomil Study) study is a randomized, parallel study to determine the relative effects of suppressing the renin-angiotensin system (RAS) with the angiotensin receptor antagonist olmesartan medoxomil versus suppressing sympathetic drive with the beta-adrenoceptor antagonist atenolol on remodeling of the subcutaneous small resistance vessel. Remodeling of small resistance vessels may be the earliest pathologic finding associated with hypertension. It may predate the onset of clinically apparent hypertension. METHODS: In this study, 100 patients with stage I hypertension are characterized at baseline before being treated for 1 year to obtain a goal BP of less than 140/90 mm Hg as defined by Joint National Committee (JNC)-7. Resistance vessel remodeling is determined using the gluteal fat biopsy technique in the hypertensive patients and a group of normotensive healthy volunteers. Additionally, efforts will be made to define whether noninvasive hemodynamic parameters, retinal vessel measurement changes, or biologic markers may predict and track the underlying vascular morphologic and physiologic changes induced by either regimen during the 12-month treatment period. RESULTS: The primary endpoint will be the degree of vascular remodeling as obtained from percutaneous biopsy of gluteal subcutaneous resistance vessels in each of two treatment arms compared with the normal volunteers. The design of the study and the pertinent baseline characteristics of these patients with uncomplicated essential hypertension are presented. CONCLUSION: The suppression of the RAS by the blockade of angiotensin II type 1 (AT(1)) receptors may demonstrate remodeling effects on the ubiquitous small resistance vessels similar to that seen in the myocardium and renal glomeruli, thus affording more complete end-organ protection.

Adult↗
PubMed2005

Peroxisome proliferator-activated receptor gamma regulates angiotensin II-stimulated phosphatidylinositol 3-kinase and mitogen-activated protein kinase in blood vessels in vivo.

Angiotensin (Ang) II is implicated in hypertension, vascular remodeling, and insulin resistance. Peroxisome proliferator-activated receptor (PPAR) gamma activators increase insulin sensitivity and improve Ang II-induced vascular remodeling. We evaluated the effects of the PPAR-gamma activator rosiglitazone on Ang II signaling in aorta and mesenteric arteries. Rats received Ang II by subcutaneous infusion and/or rosiglitazone per os for 7 days. Blood pressure rise in Ang II-infused rats was attenuated by rosiglitazone. Ang II significantly increased Ang II type 1 receptor expression in the mesenteric arteries (P<0.001), whereas that of the aorta was decreased (P<0.05), changes which were reversed by rosiglitazone. Akt activity was increased by Ang II and returned to basal levels under rosiglitazone in both vascular beds. However, Ang II-induced extracellular signal-regulated kinase 1/2 activity increased in aorta but not in mesenteric vessels (P<0.001), where 4E-binding protein 1 activity was significantly increased by Ang II and inhibited by PPAR-gamma activation. In response to Ang II, Src homology (SH) 2-containing inositol phosphatase 2 activity was increased (P<0.05) in both vascular beds. In conclusion, PPAR-gamma activator rosiglitazone attenuated Ang II-induced blood pressure elevation and intracellular signaling on aorta and mesenteric vessels. There was differential inhibition of Ang II type 1 receptor receptors/phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 in both vessels. Effects of PPAR-gamma activators on these pathways could contribute to regression of vascular remodeling in models of hypertension and diabetes and, accordingly, in hypertensive diabetic patients.

Angiotensin II↗
PubMed2005

Role of angiotensin type-1 and angiotensin type-2 receptors in the expression of vascular integrins in angiotensin II-infused rats.

Angiotensin II plays an important role in vascular remodeling through effects that involve, in part, interactions of vascular smooth muscle cells with extracellular matrix via integrins, which belong to a family of transmembrane receptors. We hypothesized that angiotensin (Ang) II regulates expression of vascular integrins and their ligands in experimental hypertension. Rats were infused subcutaneously with Ang II and received angiotensin type-1 (AT1) receptor blocker losartan, the AT1/angiotensin type-2 (AT2) [Sar1-Ile8]-Ang II, or the vasodilator hydralazine for 7 days. Osteopontin and integrin subunit expression were evaluated immunohistochemically. Ang II enhanced vascular alpha8, beta1, beta3 integrins and osteopontin expression, which were significantly reduced by losartan, [Sar1-Ile8]-Ang II, and hydralazine. Although Ang II increased vascular alpha5 subunit expression, this was additionally increased by losartan. Losartan was the only treatment that induced alpha1 subunit expression. These results demonstrate that AT1 and AT2 receptors have countervailing effects on vascular integrin subunit expression that may influence their effects on vascular remodeling and extracellular matrix composition.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed2005

c-Src-dependent nongenomic signaling responses to aldosterone are increased in vascular myocytes from spontaneously hypertensive rats.

Aldosterone plays an important role in the pathogenesis of hypertension. We previously demonstrated that nongenomic signaling by aldosterone in vascular smooth muscle cells occurs through c-Src-dependent pathways. Here we tested the hypothesis that upregulation of c-Src by aldosterone plays a role in increased mitogen-activated protein (MAP) kinase activation, [3H]-proline incorporation, and NADPH-driven generation of reactive oxygen species, thereby inducing cell growth, collagen production, and inflammation, respectively, in vascular smooth muscle cells from spontaneously hypertensive rats. The time course of c-Src phosphorylation by aldosterone was shifted to the left in vascular myocytes from hypertensive animals. Aldosterone rapidly increased phosphorylation of p38 MAP kinase and extracellular signal-regulated kinase with significantly greater effects in cells from spontaneously hypertensive rats versus control cells (P<0.05). Aldosterone increased NADPH oxidase activity with significantly greater responses in vascular smooth muscle cells from hypertensive animals (P<0.05). These events were associated with enhanced [3H]proline incorporation (index of collagen synthesis) in cells from spontaneously hypertensive rats (P<0.05). The NADPH oxidase activity increase, collagen synthesis, c-Src, and MAP kinase phosphorylation induced by aldosterone were significantly reduced by eplerenone (selective mineralocorticoid receptor blocker) and PP2 (selective c-Src inhibitor). In conclusion, nongenomic signaling by exogenous aldosterone, mediated through c-Src, is increased in vascular smooth muscle cells from spontaneously hypertensive rats. Upregulation of c-Src signaling may be important in the profibrotic and proinflammatory actions of aldosterone in this genetic model of hypertension.

Aldosterone↗
PubMed2005

PPAR-gamma inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1.

The present study evaluated the effects of peroxisome proliferator-activated receptor (PPAR)-gamma activators on ANG II-induced signaling pathways and cell growth. Vascular smooth muscle cells (VSMC) derived from rat mesenteric arteries were treated with ANG II, with/without the AT1 receptor blocker valsartan or the AT2 receptor blocker PD-123319, after pretreatment for 24 h with the PPAR-gamma activators 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) or rosiglitazone. Both 15d-PGJ2 and rosiglitazone decreased ANG II-induced DNA synthesis. Rosiglitazone treatment increased nuclear PPAR-gamma expression and activity in VSMC. However, rosiglitazone did not alter expression of PPAR-alpha/beta, ERK 1/2, Akt, or ANG II receptors. 15d-PGJ2 and rosiglitazone decreased ERK 1/2 and Akt peak activity, both of which were induced by ANG II via the AT1 receptor. Rosiglitazone inhibited ANG II-enhanced phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), as well as Src homology (SH) 2-containing inositol phosphatase 2 (SHIP2). PPAR-gamma activation reduced ANG II-induced growth associated with inhibition of ERK 1/2, Akt, 4E-BP1, and SHIP2. Modulation of these pathways by PPAR-gamma activators may contribute to regression of vascular remodeling in hypertension.

Angiotensin II↗
PubMed2005

Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury.

OBJECTIVE: Angiotensin (Ang) II-induced vascular damage may be partially mediated by reactive oxygen species generation and inflammation. Homozygous osteopetrotic mice (Op/Op), deficient in macrophage colony-stimulating factor (m-CSF), exhibit reduced inflammation. We therefore investigated Ang II effects on vascular structure, function, and oxidant stress generation in this model. METHODS AND RESULTS: Adult Op/Op, heterozygous (Op/+), and wild type (+/+) mice underwent 14-day Ang II (1000 ng/kg per minute) or saline infusion. Blood pressure (BP) was assessed by radiotelemetry, mesenteric resistance artery vascular reactivity was studied on a pressurized myograph, and vascular superoxide and NAD(P)H oxidase activity by lucigenin chemiluminescence. Ang II increased BP in Op/+ and +/+ mice but not in Op/Op. Ang II-treated Op/+ and +/+ mice showed reduced acetylcholine-mediated relaxation (maximal relaxation, respectively, 64% and 67% versus 84% and 93% in respective controls; P<0.05), which was unaffected by L-NAME. Ang II-infused Op/Op mice arteries showed significantly less endothelial dysfunction than vehicle-infused counterparts (maximal relaxation 87% versus 96% in shams). Resistance arteries from Ang II-infused +/+ and Op/+ mice had significantly increased media-to-lumen ratio and media thickness, neither of which was altered in Op/Op mice compared with untreated littermates. Vascular media cross-sectional area, NAD(P)H oxidase activity and expression, and vascular cell adhesion molecule (VCAM)-1 expression were significantly increased by Ang II only in +/+ mice (P<0.05). CONCLUSIONS: m-CSF-deficient mice (Op/Op) developed less endothelial dysfunction, vascular remodeling, and oxidative stress induced by Ang II than +/+ littermates, suggesting a critical role of m-CSF and proinflammatory mediators in Ang II-induced vascular injury.

Angiotensin II↗
PubMed2005

Combined angiotensin II type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries.

We investigated the role of angiotensin II type 1 (AT1) and AT2 receptors, matrix metalloproteinases (MMPs), and extracellular matrix (ECM) components involved in vascular remodeling of resistance arteries induced by angiotensin II (Ang II). Sprague-Dawley rats received Ang II (120 ng/kg per minute SC) +/- the AT1 antagonist losartan (10 mg/kg per day PO), the AT1/AT2 antagonist Sar1-Ile8-Ang II (Sar-Ile; 10 microg/kg per minute SC), or hydralazine (25 mg/kg per day PO) for 7 days. Structure and mechanical properties of small mesenteric arteries were evaluated on a pressurized myograph. Ang II increased growth index (+21%), which was partially decreased by losartan (-11%) and abrogated by Sar-Ile. Hydralazine markedly increased growth index (+32%) despite systolic blood pressure (BP) lowering, suggesting a BP-independent effect of Ang II on vascular growth. Elastic modulus was increased by Sar-Ile compared with Ang II and control. Vascular type I collagen was reduced (P<0.05), whereas fibronectin increased significantly with Sar-Ile. Vascular tissue inhibitor of metalloproteinase-2 binding to MMP-2 was abrogated by Sar-Ile, but MMP-2 activity was significantly increased compared with losartan, Ang II, and controls. Thus, AT1 blockade exerted antigrowth effects and reduced stiffness of small resistance arteries by decreasing nonelastic fibrillar components (collagen and fibronectin). Concomitant AT1/AT2 blockade prevented growth, reduced collagen type I and elastin deposition but increased vascular stiffness, fibronectin, and MMP-2 activity. These results demonstrate opposing roles of AT1 receptors that increase fibronectin and vascular stiffness and AT2 receptors that decrease MMP-2 and increase elastin. Changes in vascular wall mechanics, ECM deposition, and MMP activity are thus modulated differentially by Ang II receptors.

1-Sarcosine-8-Isoleucine Angiotensin II↗