Effect of insulin and angiotensin II receptor subtype-1 antagonist on myocardial remodelling in rats with insulin-dependent diabetes mellitus

Jaroudi, Wael Al; Nuwayri-Salti, Nuha; Usta, Jinan; Zwainy, Darine S; Karam, Chehade N.; Bitar, Khalil M.; Bikhazi, Anwar B.

doi:10.1097/00004872-200502000-00021

Cited by 20 publications

(24 citation statements)

References 28 publications

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“…In addition, both the western blot and the immunofluorescence results of the DIL group indicated definite reduction of IGF-1R expression and localization at the heart level. Therefore these results can postulate that IGF-1R expression, and the binding episode with its substrate may be playing a key role in cardiac protection and prevention of damage in this treatment modality [8]. In conclusion, these findings reinforce the…”

Section: Discussionsupporting

confidence: 75%

“…Summed together, the increased IGF-1 affinity to its receptor at both the coronary endothelial and cardiomyocyte levels can be considered as one of the late alterations imposed by diabetes on the heart tissue. This alteration could be aiding in the wide hypertrophic changes seen in late stage diabetic heart [8]. On the contrary, insulin and losartan treatment was able to reduce this affinity, and thus may delay, or even prevent this type of myocardial remodeling as observed in our previous studies [8].…”

Section: Discussionmentioning

confidence: 66%

“…Cardiomyopathy, a specific heart muscle dysfunction that occurs independently of coronary artery disease, may lead to heart failure [7]. Furthermore, our laboratory found that cardiomyopathic alterations in streptozotocin (STZ)-induced diabetic rats usually start with apoptosis early after diabetes induction and end with hypertrophy and broad cardiomyopathic damage [8]. Insulin actions are mediated through binding to its tyrosine kinase receptor leading to tyrosine phosphorylation of many proteins, including the IRS-1 and IRS-2 [9].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we found that in STZ-induced diabetic rats, the co-treatment with insulin and losartan was almost able to totally prevent myocardial remodeling [8]. We also reported that this treatment modality could improve cardiac contraction as well as coronary blood flow in STZ-induced diabetic rats through the modification of the affinity of endothelin-1 (ET-1) to its receptor subtypes ET A -R and ET B -R [19].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Insulin and Losartan on Modulation of Insulin-Like Growth Factor 1 Receptor at Heart Level in Diabetic Rats

Bikhazi¹,

Maharsy²,

Kadi³

et al. 2007

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This study investigates insulin-like growth factor-1 receptor (IGF-1R) modulation in hearts of streptozotocininduced diabetic rats treated with insulin/angiotensin-II receptor subtype-1 blocker (AR 1 B), losartan. Male rats were divided into: normal (N), losartan-treated normal (NL), diabetic (D), insulin-treated diabetic (DI), losartan-treated diabetic (DL), and insulin/losartan co-treated diabetic (DIL) groups. Thirty days post-treatment, rats underwent heart perfusion using [I 125 ]-labeled IGF-1 to assess receptor-binding affinity on coronary endothelial cells (CE) and cardiomyocytes (CM). This revealed an increase in binding affinity of IGF-1 to its receptor on CE in all groups compared to N. On CM, binding affinity increased in D, DI, and DL compared to N, but was almost normalized in DIL. Western blot analyses and immunohistochemistry done on heart tissues showed decrease in IGF-1R density in DIL versus remaining groups. These results demonstrate a complex interaction between insulin, angiotensin-II, and IGF-1, and mass blockade of myocardial remodeling by AR 1 B treatment in diabetic state.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Insulin and Losartan on Modulation of Insulin-Like Growth Factor 1 Receptor at Heart Level in Diabetic Rats

Bikhazi¹,

Maharsy²,

Kadi³

et al. 2007

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“…All the animals were weighed weekly and blood glucose levels were determined (Al-Jaroudi et al 2005).…”

Section: Body Weight and Blood Sugarmentioning

confidence: 99%

Effect of Systemic Insulin and Angiotensin II Receptor Subtype-1 Antagonist on Endothelin-1 Receptor Subtype(s) Regulation and Binding in Diabetic Rat Heart

et al. 2005

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This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ET(A)-Rs/ET(B)-Rs, at the coronary endothelium (CE) and cardiomyocyte (CM) sites. It is carried out in normal and normotensive rats with streptozotocin-induced diabetes mellitus receiving different treatment modalities. Normal rats were divided into two groups, namely a placebo (N) and a losartan-treated (NL), and diabetic rats into four groups receiving placebo (D), insulin-treated (DI), losartan-treated (DL), and insulin/losartan-treated (DIL) respectively. Binding kinetics of ET-1 to ET(A)-Rs/ET(B)-Rs on CE and CMs were assessed in the above groups to try to explain the effect of therapeutic doses of an angiotensin II receptor subtype-1 blocker on the dynamics of this ligand and its receptor in insulin supplemented diabetic animals. Each group was divided into two subgroups: CHAPS-untreated and CHAPS-treated rat hearts perfused with [125I]ET-1 to respectively estimate ET-1 binding affinity (tau = 1/k-n) to its receptor subtype(s) on CE and CMs using mathematical modeling describing a 1:1 reversible binding stoichiometry. Heart perfusion results revealed that insulin treatment significantly decreased tau on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in tau value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized tau on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ET(A)-R density in all diabetic groups. However, significant decrease in ET(B)-R density was observed in all groups compared to the normal, and was reconfirmed by immunohistochemical analysis. In conclusion, coadministration of insulin and losartan in nonhypertensive animals suffering from diabetes type 1 may offer new cardiac protection benefits by improving coronary blood flow and cardiomyocyte contractility through modulating ET-1 receptor subtypes density and affinity at CE and CM sites.

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Angiotensin II: A hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks

Schlüter

Wenzel

2008

Pharmacology & Therapeutics

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Effect of insulin and angiotensin II receptor subtype-1 antagonist on myocardial remodelling in rats with insulin-dependent diabetes mellitus

Abstract: Addition of losartan to the standard insulin treatment in non-hypertensive animals with IDDM offers new benefits concerning cardiac protection and prevention of damage. This may be attributed, in part, to insulin receptor density and sensitization.

Cited by 20 publications

References 28 publications

Effect of Insulin and Losartan on Modulation of Insulin-Like Growth Factor 1 Receptor at Heart Level in Diabetic Rats

Effect of Insulin and Losartan on Modulation of Insulin-Like Growth Factor 1 Receptor at Heart Level in Diabetic Rats

Effect of Systemic Insulin and Angiotensin II Receptor Subtype-1 Antagonist on Endothelin-1 Receptor Subtype(s) Regulation and Binding in Diabetic Rat Heart

Angiotensin II: A hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks

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