Cardiovascular protective role of a low-dose antihypertensive combination in obese Zucker rats

Toblli, Jorge Eduardo; Derosa, G.; Rivas, Carlos; Cao, Gabriel; Piorno, Pablo; Pagano, Patricia; Forcada, Pedro

doi:10.1097/00004872-200303000-00028

Cited by 27 publications

(23 citation statements)

References 49 publications

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“…However, we and others have suggested that the elevation of endothelin-1 or angiotensin II, or the activation of PKC␤ isoform can increase the Thr/ser phosphorylation of insulin receptors, IRS, and p85/PI3K, which will all decrease the phosophorylation of Akt, and inhibit insulin's actions. 12,30,31 Further studies are needed to pinpoint the sites of the inhibition in the myocardium.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Vascular Endothelial Growth Factor Expression and Vascularization in the Myocardium by Insulin Receptor and PI3K/Akt Pathways in Insulin Resistance and Ischemia

Opland

Way

et al. 2006

ATVB

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Objective-This study characterized the role of insulin receptors and resistance on vascular endothelial growth factor (VEGF) expression and myocardial vascularization in physiological conditions and after ischemia. Methods and Results-Cardiac microvascular density was reduced by 30% in insulin-resistant Zucker fatty rats versus lean controls. This was associated with a parallel 40% inhibition of insulin-stimulated activation of both Akt and VEGF expression in the myocardium and cardiomyocytes. In contrast, the activation of Erk1/2 by insulin remained unchanged. In cultured cardiomyocytes, insulin or insulin-like growth factor (IGF)-1 increased VEGF mRNA and protein expression by 2-fold. Inhibition of PI3K/Akt, especially Akt2-mediated cascades but not the Ras/MEK/Erk pathway, using chemical inhibitors, dominant negative adenoviral constructs, or siRNA approaches suppressed VEGF mRNA expression by insulin. Ventricular tissues from muscle insulin receptor knockout (MIRKO) mice, which lack insulin receptors in the myocardium, have significant reductions in insulin but not IGF-1 signaling, VEGF expression, and vascular density before and after ischemia versus controls. Key Words: cardiomyocyte Ⅲ collateral circulation Ⅲ diabetes Ⅲ insulin resistance Ⅲ vascularization Ⅲ VEGF P atients with type 2 diabetes and insulin resistance have high morbidity and mortality rates, caused mainly by ischemic heart disease (IHD), 1 partly caused by reduced collateral vessel formation in response to ischemia in the myocardium. 2,3 Patients with concomitant IHD and diabetes have reduced microvessel density in the myocardium as compared with those with IHD alone or healthy subjects. 4 Microvessel homeostasis is determined by multiple factors, including the expression and actions of vascular endothelial growth factor (VEGF), a potent angiogenic factor. 5 Ventricular cardiomyocytes are a rich source of VEGF production that significantly affects the development and function of cardiac vasculature. 6 We and others have previously shown that diabetes and insulin resistance are associated with attenuated cardiac VEGF expression, which may decrease capillary density in the myocardium in diabetic and insulin resistant states, 7 leading to cardiac dysfunction 8 . Conclusions-InsulinInduction of VEGF expression by insulin has been reported in several cell types including vascular smooth muscle cells, 9 epithelial cells, 10 and fibroblasts, 11 but not in cardiomyocytes or in vivo. We have reported that there is a selective loss of insulin's signaling via PI3K/Akt pathway in the vascular endothelium in insulin-resistant states, which can cause abnormalities in gene expression such as the decreased expression of endothelial nitric oxide synthase. 12 However, insulin has not been reported to regulate the vascularization of myocardium directly. We propose that insulin's signaling and actions may also be decreased in the myocardium and contribute to the reduced expression of VEGF in insulin resistance. Furthermore, we have assessed the importance of i...

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Section: Discussionmentioning

confidence: 99%

Regulation of Vascular Endothelial Growth Factor Expression and Vascularization in the Myocardium by Insulin Receptor and PI3K/Akt Pathways in Insulin Resistance and Ischemia

Opland

Way

et al. 2006

ATVB

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“…87,88 Interestingly, this antihypertensive combination also improved insulin sensitivity. 87 In nondiabetic patients with hypercholesterolemia, 8 to 12 months of simvastatin therapy increased coronary flow reserve. 89 Lifestyle changes can also improve tissue perfusion.…”

Section: Levy Et Al Microcirculation and Cardiovascular Risk Factorsmentioning

confidence: 94%

Impaired Tissue Perfusion

et al. 2008

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“…Echocardiographic evaluation of the left ventricle Transthoracic echocardiograms were obtained from each rat, without anesthesia, using a Toshiba echocardiographic system (Toshiba, Tokyo, Japan) with a 7.5-MHz transducer at baseline and at the end of the experiment [20]. M-mode and bidimensional echocardiography was performed in minor axis, at the level of papillary muscle.…”

Section: Oxidative Stress Parameters' Evaluation In Heartmentioning

confidence: 99%

Cardiovascular protective effects of nebivolol in Zucker diabetic fatty rats

Toblli

Cao

Rivas

et al. 2010

Journal of Hypertension

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Cardiovascular protective role of a low-dose antihypertensive combination in obese Zucker rats

Abstract: These results suggest that LDC of PER + IND can control cardiovascular damage in OZR providing an additional help in the metabolic scenario likewise.

Cited by 27 publications

References 49 publications

Regulation of Vascular Endothelial Growth Factor Expression and Vascularization in the Myocardium by Insulin Receptor and PI3K/Akt Pathways in Insulin Resistance and Ischemia

Regulation of Vascular Endothelial Growth Factor Expression and Vascularization in the Myocardium by Insulin Receptor and PI3K/Akt Pathways in Insulin Resistance and Ischemia

Impaired Tissue Perfusion

Cardiovascular protective effects of nebivolol in Zucker diabetic fatty rats

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