Role of ANG II in coronary capillary angiogenesis at the insulin-resistant stage of a NIDDM rat model

Jesmin, Subrina; Hattori, Yoshiyuki; Sakuma, Ichiro; Mowa, Chishimba Nathan; Kitabatake, Akira

doi:10.1152/ajpheart.00299.2002

Cited by 29 publications

(35 citation statements)

References 43 publications

(49 reference statements)

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“…We also showed a significant increase in cardiac collagen deposition in these diabetic rats, as reported in previous studies from this laboratory. 18,19 Support for our findings is also provided by the results of other investigators who demonstrated that cardiac fibrosis could be promoted from the prediabetic state in OLETF rats. 4 We found that TGF-␤ 1 was highly expressed in coronary vessels and the perivascular area, as well as in cardiomyocytes in the OLETF rat heart.…”

Section: Discussionsupporting

confidence: 88%

“…16 Our recent work found that angiotensin II labeling and AT 1 receptor expression in coronary vessels were profoundly increased in Otsuka LongEvans Tokushima Fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus (NIDDM), 17 compared with nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. 18 However, it is not known whether AT 1 receptor blockade can produce a favorable effect on altered expression of molecules associated with ECM turnover and regulation that might contribute to the development of coronary remodeling seen in diabetes. This study aimed to gain insight into the molecular mechanisms underlying coronary remodeling of ECM in the heart observed at the insulin-resistant stage of NIDDM in OLETF rats, and we sought to evaluate the therapeutic effect of candesartan, an AT 1 receptor blocker, on the altered expression of molecules involved in coronary matrix remodeling in diabetic animals.…”

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confidence: 99%

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Role of Angiotensin II in Altered Expression of Molecules Responsible for Coronary Matrix Remodeling in Insulin-Resistant Diabetic Rats

Jesmin

Sakuma

Hattori

et al. 2003

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Objective-Coronary remodeling based on collagen abnormalities in diabetes might be associated with potential interactions between the matrix metalloproteinase (MMP) system, which regulates extracellular matrix turnover, and the fibrinolytic system, which is involved in the fibrin degradation process. We characterized the profiles of the MMP and fibrinolytic systems in insulin-resistant diabetic rat hearts. Methods and Results-By immunohistochemistry and in situ hybridization, transforming growth factor-␤ 1 (TGF-␤ 1 ) expression increased in coronary vessels, the perivascular area, and cardiomyocytes in diabetic rat hearts. Increased expression of plasminogen activator inhibitor-1 (PAI-1) in coronary vessels and the perivascular area was evident in diabetic hearts. In contrast, diabetic hearts exhibited reduced activity and expression of MMP-2 and decreased expression of membrane type-1 MMP (MT1-MMP). Both intravascular and extravascular collagen type I and III immunoreactivity and fibrin deposition were seen in diabetic coronary vessels. These alterations were reversed to nondiabetic levels by the angiotensin II type 1 receptor blocker candesartan, which prevented the development of perivascular fibrosis observed after Masson's trichrome staining. Key Words: matrix remodeling Ⅲ matrix metalloproteinases Ⅲ diabetes Ⅲ plasminogen activator inhibitor-1 Ⅲ angiotensin II C ollagen in the normal adult heart serves several important functions, which include providing a supportive structural lattice for cardiomyocytes and coronary vessels and connecting individual myocytes and myofibrillar bundles to integrate individual cardiac contractions. However, a disproportionate increase in collagen accretion or collagen resorption from normal levels can cause defects in the function and supporting structural lattice of the heart. It has been widely known that diabetes is associated with alterations in extracellular matrix (ECM) turnover and regulation. 1 Pathologic remodeling characterized by ECM deposition might contribute to cardiovascular complications that are the leading cause of morbidity and mortality in diabetic patients. 2 Alteration in diastolic filling of the left ventricle (LV) associated with reciprocal changes in the LV collagen gene and accumulation of cardiac collagen in diabetic rats 3,4 suggest that increased interstitial cardiac collagen might cause cardiac fibrosis and result in greater LV stiffness and decreased LV wall compliance, thus leading to diastolic dysfunction and eventual heart failure in diabetes. Conclusions-InClearly, an imbalance between ECM production and degradation must underlie the process of ECM expansion, but these dynamics in the diabetic heart are poorly understood. Matrix metalloproteinases (MMPs) are primarily responsible for the breakdown of ECM proteins such as collagen and elastin, and their activity is tightly regulated by tissue inhibitors of MMPs (TIMPs). 5,6 Recent experimental evidence indicates that expression of MMP-2 and MMP-9 is altered in renal tissues and vasculature fr...

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Section: Discussionsupporting

confidence: 88%

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confidence: 99%

Role of Angiotensin II in Altered Expression of Molecules Responsible for Coronary Matrix Remodeling in Insulin-Resistant Diabetic Rats

Jesmin

Sakuma

Hattori

et al. 2003

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“…Systemic ACE and AngII levels in diabetic patients are not elevated, although subsets of patients may have elevated ACE activity if they carry the ACE DD polymorphism (45,46). Another possibility is that diabetes stimulates local increases of AngII or AngII receptors within specific tissues or compartments (47). It is now accepted that most tissues contain all of the components of the renin-angiotensin system and are able to generate tissue AngII independent of the circulation.…”

Section: Discussionmentioning

confidence: 99%

Loss of Heparan N-Sulfotransferase in Diabetic Liver

et al. 2005

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The basis for accelerated atherosclerosis in diabetes is unclear. Diabetes is associated with loss of heparan sulfate (HS) from the liver, which may impede lipoprotein clearance and thereby worsen atherosclerosis. To study hepatic HS loss in diabetes, we examined regulation of HS N-deacetylase/N-sulfotransferase-1 (NDST), a key enzyme in hepatic HS biosynthesis. Hepatic NDST mRNA, protein, and enzymatic activity were suppressed by >50% 2 weeks after induction of type 1 diabetes in rats. Treatment of diabetic rats with enalapril, an ACE inhibitor, had no effect on hyperglycemia or hepatic NDST mRNA levels, yet increased hepatic NDST protein and enzymatic activity. Similar results were obtained in diabetic animals treated with losartan, which blocks the type 1 receptor for angiotensin II (AngII). Consistent with these findings, diabetic livers exhibited increased ACE expression, and addition of AngII to cultured hepatoma cells reduced NDST activity and protein. We conclude that diabetes substantially suppresses hepatic NDST mRNA, protein, and enzymatic activity. AngII contributes to suppression of NDST protein and enzymatic activity, whereas mRNA suppression occurs independently. Suppression of hepatic NDST may contribute to diabetic dyslipidemia, and stimulation of NDST activity by AngII inhibitors may provide cardiovascular protection. Diabetes 54:1116 -1122, 2005

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“…Thus the effect of benidipine therapy to normalize the upregulated ET-1 system in OLETF rat hearts may be partly due to the modestly lowering action on blood pressure. Furthermore, we have previously found that angiotensin II is upregulated in coronary vessels of the OLETF rat heart, and the blockade of angiotensin II type 1 receptors with candesartan can greatly reverse diabetes-induced cardiac remodeling (24). In this regard, angiotensin II can induce ET-1 gene expression in rat aortic smooth muscle cells (21), and angiotensin-converting enzyme inhibition can decrease circulatory ET-1 levels in lean noninsulin-dependent diabetic patients (16).…”

Section: Discussionmentioning

confidence: 98%

Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats

Jesmin¹,

Hattori²,

Maeda³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Role of ANG II in coronary capillary angiogenesis at the insulin-resistant stage of a NIDDM rat model

Cited by 29 publications

References 43 publications

Role of Angiotensin II in Altered Expression of Molecules Responsible for Coronary Matrix Remodeling in Insulin-Resistant Diabetic Rats

Role of Angiotensin II in Altered Expression of Molecules Responsible for Coronary Matrix Remodeling in Insulin-Resistant Diabetic Rats

Loss of Heparan N-Sulfotransferase in Diabetic Liver

Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats

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