Increased aortic stiffness in the insulin-resistant Zucker<i>fa/fa</i>rat

Sista, Akhilesh K.; O’Connell, Mary K.; Hinohara, Tomoya; Oommen, Santosh S.; Fenster, Brett E.; Glassford, Alexander J.; Schwartz, Eric A.; Taylor, Charles A.; Reaven, Gerald M.; Tsao, Philip S.

doi:10.1152/ajpheart.00134.2005

Cited by 35 publications

(34 citation statements)

References 35 publications

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“…Diabetes causes overproduction of cardiac ECM, which contributes to diastolic dysfunction, and ECM overaccumulation has been reported in the diabetic rat heart (Martin et al, 2005). Studies have shown that collagen IV and fibronectin coalesce around smooth muscle cells in the aortic media (Sista et al, 2005). In this study, mRNAs corresponding to these major ECM components were increased in experimental diabetes (Fig.…”

Section: Discussionsupporting

confidence: 62%

Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

Gong¹,

Lu²,

Chen³

et al. 2006

Molecular Pharmacology

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Most patients with diabetes die from cardiac or arterial disease, for which there are limited therapeutic options. Free Cu 2ϩ ions are strongly pro-oxidant, and chelatable-Cu II is increased in the diabetic heart. We reported previously that treatment by Cu IIselective chelation with triethylenetetramine (TETA) evokes elevated urinary Cu II in diabetic rats and humans in whom it also improved hallmarks of established left ventricular (LV) disease. Here, we treated diabetic rats with TETA and evaluated its ability to ameliorate Cu 2ϩ -mediated LV and arterial damage by modifying the expression of molecular targets that included transforming growth factor (TGF)-␤1, Smad4, extracellular matrix (ECM) proteins, extracellular superoxide dismutase (EC-SOD), and heparan sulfate (HS). Eight-weeks of TETA treatment significantly improved cardiac diastolic function but not [glucose] plasma in diabetic animals. LV and aortic mRNAs corresponding to TGF-␤1, Smad4, collagen types I, III, and IV, and fibronectin-1, and plasminogen activator inhibitor-1, were elevated in untreated diabetic animals and normalized after TETA treatment. EC-SOD mRNA and protein, and [HS] tissue were significantly decreased in diabetes and restored by drug treatment. Candidate molecular mechanisms by which TETA could ameliorate diabetic cardiac and arteriovascular disease include the suppression of an activated TGF-␤/Smad signaling pathway that mediates increased ECM gene expression and restoration of normal EC-SOD and HS regulation. These findings are relevant to the restoration toward normal by TETA treatment of cardiac and arterial structure and function in diabetes.

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Section: Discussionsupporting

confidence: 62%

Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

Gong¹,

Lu²,

Chen³

et al. 2006

Molecular Pharmacology

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“…[23][24][25] In addition, mechanical testing of the aortas from obese Zucker (fa/fa) rats showed greater stiffness in the circumferential and longitudinal directions. 26 However, the mechanistic insight into the link between obesity and aortic stiffening has been lacking.…”

Section: Discussionmentioning

confidence: 99%

Increased Aortic Stiffness and Attenuated Lysyl Oxidase Activity in Obesity

Chen¹,

Tsai²,

Tai

et al. 2013

ATVB

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Objective-One potential mechanism through which obesity exerts adverse effects on the vascular system is by increasing aortic stiffness, a change known to be predictive of increased cardiovascular mortality. The aim of this study was to investigate the pathophysiology that links obesity to aortic stiffening. Approach and Results-Obese (ob/ob) mice were used to examine physical, morphological, and molecular changes in the aorta in response to obesity. ob/ob mice had increased aortic pulse wave velocity and tissue rigidity. ob/ob aorta exhibited decreases of lysyl oxidase (LOX) activity and cross-linked elastin, and increases of elastin fragmentation and elastolytic activity. The aortas of ob/ob mice were surrounded by a significant amount of proinflammatory and pro-oxidative perivascular adipose tissue. In vitro studies revealed that the conditioned medium from differentiated adipocytes or the perivascular adipose tissue of ob/ob mice attenuated LOX activity. Furthermore, inhibition of LOX in wild-type lean mice caused elastin fragmentation and induced a significant increase in pulse wave velocity. Finally, we found that obese humans had stiffer arteries and lower serum LOX levels than do normal-weight humans. Conclusion-Our results demonstrated that obesity resulted in aortic stiffening in both humans and mice, and established a causal relationship between LOX downregulation and aortic stiffening in obesity.

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“…RASMCs were harvested by enzymatic digestion from rat aortas as previously described (53). Cells were cultured in Dulbecco modified Eagle medium with 10% fetal bovine serum, 10 units/ml penicillin, and 100 μg/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis

Chun¹,

Ali²,

Kojima³

et al. 2008

J. Clin. Invest.

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222

269

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Apelin and its cognate G protein-coupled receptor APJ constitute a signaling pathway with a positive inotropic effect on cardiac function and a vasodepressor function in the systemic circulation. The apelin-APJ pathway appears to have opposing physiological roles to the renin-angiotensin system. Here we investigated whether the apelin-APJ pathway can directly antagonize vascular disease-related Ang II actions. In ApoE-KO mice, exogenous Ang II induced atherosclerosis and abdominal aortic aneurysm formation; we found that coinfusion of apelin abrogated these effects. Similarly, apelin treatment rescued Ang II-mediated increases in neointimal formation and vascular remodeling in a vein graft model. NO has previously been implicated in the vasodepressor function of apelin; we found that apelin treatment increased NO bioavailability in ApoE-KO mice. Furthermore, infusion of an NO synthase inhibitor blocked the apelin-mediated decrease in atherosclerosis and aneurysm formation. In rat primary aortic smooth muscle cells, apelin inhibited Ang II-mediated transcriptional regulation of multiple targets as measured by reporter assays. In addition, we demonstrated by coimmunoprecipitation and fluorescence resonance energy transfer analysis that the Ang II and apelin receptors interacted physically. Taken together, these findings indicate that apelin signaling can block Ang II actions in vascular disease by increasing NO production and inhibiting Ang II cellular signaling.

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Increased aortic stiffness in the insulin-resistant Zuckerfa/farat

Cited by 35 publications

References 35 publications

Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

Increased Aortic Stiffness and Attenuated Lysyl Oxidase Activity in Obesity

Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis

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