Chronic Hyperglycemia Attenuates Coronary Collateral Development and Impairs Proliferative Properties of Myocardial Interstitial Fluid by Production of Angiostatin

Weihrauch, Dorothée; Lohr, Nicole L.; Mraović, Boris; Ludwig, Lynda M.; Chilian, William M.; Pagel, Paul S.; Warltier, David C.; Kersten, Judy R.

doi:10.1161/01.cir.0000129225.67353.1f

Cited by 68 publications

(67 citation statements)

References 24 publications

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“…Weirauch et al demonstrated reduced collateral-dependent perfusion in chronically instrumented dogs under hyperglycemic conditions and demonstrated the critical role of angiostatin in inhibiting collateral vessel formation in response to repetitive coronary occlusion, both in vivo and in vitro. 27 We have reproduced some of their findings in a clinically relevant model of diabetes and chronic myocardial ischemia by demonstrating a profound (Ͼ4-fold) increase in angiostatin expression in diabetic animals. In addition, diabetes was also associated with a 2-fold increase in endostatin expression.…”

Section: Controlmentioning

confidence: 54%

Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes

et al. 2007

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Background-Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved. Methods and Results-Diabetes was induced in male Yucatan miniswine using a pancreatic ␤-cell specific toxin, alloxan (150 mg/kg; nϭ8). Age-matched swine served as controls (nϭ8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173Ϯ14 versus 234Ϯ23 cells/hpf, Pϭ0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4Ϯ0.9-fold increase, PϽ0.001), and endostatin (2.9Ϯ0.4-fold increase, Pϭ0.03) were significantly elevated in the diabetic myocardium. Conclusions-Diabetes

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Section: Controlmentioning

confidence: 54%

Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes

et al. 2007

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“…[6][7][8] Many studies have indicated that inadequate angiogenic response to ischemia may result in severe organ damage attributable to poor collateral vessel formation and decreased new vessel formation. 9,10 The four and a half Lin11, Isl-1 and Mec-3 (LIM) domain (FHL) protein family is a newly identified group of proteins containing FHLs. This family consists of 6 members-FHL1, FHL2, FHL3, FHL4, FHL5, and activator of cAMP-responsive element modulator in testes.…”

mentioning

confidence: 99%

Deletion of FHL2 Gene Impaired Ischemia-Induced Blood Flow Recovery by Modulating Circulating Proangiogenic Cells

Huang

Chen

Lin

et al. 2013

ATVB

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Objective-The four and a half Lin11, Isl-1 and Mec-3 (LIM) domain protein 2 (FHL2) is a member of the four and a half LIM domain-only (FHL) gene family, and has been shown to play an important role in inhibiting inflammatory angiogenesis. Here, we tested the hypothesis that impaired ischemia-induced neovascularization in mice lacking FHL2 is related to a defect in proangiogenic cell mobilization and functions in vasculogenesis. Approach and Results-Unilateral hindlimb ischemia surgery was conducted in FHL2 −/− mice and wild-type (FHL2 +/+ ) mice. After hindlimb ischemia surgery, expression of FHL2 protein was noted in ischemic tissues of wild-type mice. All FHL2-null mice (100%) suffered from spontaneous foot amputation, but only 20% of wild-type mice had ischemiainduced foot amputation after ischemic surgery. Blood flow recovery was significantly impaired in FHL2 −/− mice when compared with that in wild-type mice as determined by laser Doppler imaging. Histological analysis revealed that the capillary density in the ischemic limb was increased in wild-type mice, whereas no such increase was noted in FHL2 −/− mice. Flow cytometry demonstrated that the number of CD34 + or CD34 + /Sca-1 + /Flk-1 + in peripheral blood after ischemic surgery significantly decreased in FHL2-null mice than those in wild-type mice after hindlimb ischemia surgery. FHL2 deficiency impaired ex vivo angiogenesis in mouse aortic-ring culture assay, which revealed that the mean density of the microvessels was significantly higher in the wild-type aorta than in the FHL2 −/− aorta. Western blot analysis showed that vascular endothelial growth factor (VEGF), interleukin-6, matrix metalloproteinase-2, matrix metalloproteinase-9, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 levels were significantly downregulated in ischemic muscles in FHL2-null mice compared with wild-type mice. Deletion of FHL2 protein by FHL2 small interfering RNA impaired VEGF production under hypoxia conditions, and also suppressed endothelial progenitor cell angiogenic functions, but these effects could be recovered by administration of VEGF. Conclusions-Deficiency of FHL2 impairs ischemia-induced neovascularization, and these suppressive effects may occur through a reduction in proangiogenic cell mobilization, migration, and vasculogenesis functions. The four and a half Lin11, Isl-1 and Mec-3 (LIM) domain (FHL) protein family is a newly identified group of proteins containing FHLs. This family consists of 6 members-FHL1, FHL2, FHL3, FHL4, FHL5, and activator of cAMP-responsive element modulator in testes. [11][12][13] Recent studies have indicated that human four and a half LIM-only protein family members, including FHL2, are expressed in a cell-and tissuespecific manner and participate in various cellular processes, such as regulation of gene expression, cytoarchitecture, cell adhesion, cell survival, cell mobility, transcription, and signal transduction.13,14 Increasing evidence shows that FHL2 is abundantly expressed in the vascular system, i...

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“…To test this hypothesis, the effects of high glucose treatment (46) [a condition mimicking diabetic conditions (62)] on endothelial function, O 2 •Ϫ and H 2 O 2 production, and inflammatory gene expression were compared in cultured arteries and cells of longerliving P. leucopus and shorter-living M. musculus.…”

mentioning

confidence: 99%

Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus

Labinskyy¹,

Mukhopadhyay

Tóth³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Labinskyy N, Mukhopadhyay P, Toth J, Szalai G, Veres M, Losonczy G, Pinto JT, Pacher P, Ballabh P, Podlutsky A, Austad SN, Csiszar A, Ungvari Z. Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus. Am J Physiol Heart Circ Physiol 296: H946 -H956, 2009. First published January 30, 2009 doi:10.1152/ajpheart.00693.2008.-Vascular aging is characterized by increased oxidative stress and proinflammatory phenotypic alterations. Metabolic stress, such as hyperglycemia in diabetes, is known to increase the production of ROS and promote inflammatory gene expression, accelerating vascular aging. The oxidative stress hypothesis of aging predicts that vascular cells of long-lived species exhibit lower steady-state production of ROS and/or superior resistance to the prooxidant effects of metabolic stress. We tested this hypothesis using two taxonomically related rodents, the white-footed mouse (Peromyscus leucopus) and the house mouse (Mus musculus), which show a more than twofold difference in maximum lifespan potential (8.2 and 3.5 yr, respectively). We compared interspecies differences in steady-state and high glucose (HG; 30 mmol/l)-induced production of O 2•Ϫ and H2O2, endothelial function, mitochondrial ROS generation, and inflammatory gene expression in cultured aortic segments. In P. leucopus aortas, steady-state endothelial O 2•Ϫ and H2O2 production and ROS generation by mitochondria were less than in M. musculus vessels. Furthermore, vessels of P. leucopus were more resistant to the prooxidant effects of HG. Primary fibroblasts from P. leucopus also exhibited less steady-state and HG-induced ROS production than M. musculus cells. In M. musculus arteries, HG elicited significant upregulation of inflammatory markers (TNF-␣, IL-6, ICAM-1, VCAM, and monocyte chemoattractant protein-1). In contrast, the proinflammatory effects of HG were blunted in P. leucopus vessels. Thus, increased life span potential in P. leucopus is associated with decreased cellular ROS generation and increased resistance to prooxidant and proinflammatory effects of metabolic stress, which accord with predictions of the oxidative stress hypothesis of aging.senescence; comparative biology; vascular disease; atherosclerosis AGE IS A MAJOR RISK FACTOR for cardiovascular disease, which remains the leading cause of morbidity and mortality of older Americans. Despite recent advances in the biology of aging, the factors determining successful cardiovascular aging are still not completely understood (15, 53, 54). Mammalian life span ranges 100-fold, and comparative studies (53, 54) on longlived, successfully aging animals can elucidate key cellular mechanisms that may contribute importantly to successful cardiovascular aging. We initiated a series of studies to compare mechanisms related to oxidative stress, oxidative stress resistance, and redox signaling between long-living species and shorter-living ones to test predictions of the oxidative stress t...

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Chronic Hyperglycemia Attenuates Coronary Collateral Development and Impairs Proliferative Properties of Myocardial Interstitial Fluid by Production of Angiostatin

Cited by 68 publications

References 24 publications

Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes

Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes

Deletion of FHL2 Gene Impaired Ischemia-Induced Blood Flow Recovery by Modulating Circulating Proangiogenic Cells

Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus

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