Maintenance of GLUT4 expression in smooth muscle prevents hypertension-induced changes in vascular reactivity

Atkins, Kevin B.; Seki, Yoshinori; Saha, Jharna; Eichinger, Felix; Charron, Maureen J.; Brosius, Frank C.

doi:10.14814/phy2.12299

Cited by 8 publications

(6 citation statements)

References 31 publications

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“…Murine systolic blood pressure was measured by the IITC Life Science blood pressure (tail cuff) system (Woodland Hills, CA) as described previously (100). Hematocrit was measured by CritSpin® Micro-Hematocrit centrifuge with Digital Hematocrit Reader (StatSpin ® Company).…”

Section: Methodsmentioning

confidence: 99%

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

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Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptordeficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products, and the protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and o,o′-dityrosine were examined with immunoassays and confirmed with mass spectrometry (MS). As anticipated, the CKD mice had significantly higher plasma creatinine, urea nitrogen, and intact parathyroid hormone along with lower hematocrit and body weight. On both the diet regimens, CKD mice did not have hypertension but had lower cholesterol and triglyceride levels than the control mice. Despite the lower cholesterol levels, CKD mice had increased aortic plaque areas, fibrosis, and luminal narrowing. They also exhibited increased MPO expression and activity (i.e., increased oxidized tyrosines) that co-localized with infiltrating lesional macrophages and diminished vascular reactivity. In summary, unlike non-CKD mouse models of atherosclerosis, CKD mice exhibit increased MPO expression and catalytic activity in atherosclerotic lesions, which colocalize with lesional macrophages. These results implicate macrophage-derived MPO in CKDaccelerated atherosclerosis.Chronic kidney disease (CKD) affects 15% of Americans, and cardiovascular disease (CVD) continues to be the leading cause of mortality in Myeloperoxidase oxidizes artery proteins in kidney disease2 these patients (>10-fold mortality compared to the general population) (1-6). An increased risk for CVD is evident even in milder and non-albuminuric forms of CKD and cannot be fully explained by traditional risk factors (7-10). Furthermore, control of established risk factors such as hyperlipidemia results in substantially lower risk reduction in CKD patients compared to the general population (11). Recent evidence supports the key role of nontraditional risk factors (e.g., oxidative stress) in the pathogenesis of CVD in CKD (12-17), suggesting that CKD-specific mechanisms are responsible for CVD in kidney patients.Atherosclerosis, the major cause of CVD, is a chronic inflammatory disease characterized by the infiltration of lipids and inflammatory cells, such as monocyte-derived macrophages and Tlymphocytes, into the artery wall (18). While elevated levels of low-density lipoprotein (LDL) are known to increase the risk of atherosclerosis greatly (19), in vitro studies sugges...

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Section: Methodsmentioning

confidence: 99%

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

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“…The reduced expression of GLUT4 was observed in the aorta of hypertensive rats and mice (12,180). Moreover, the loss of GLUT4 expression in VSMCs results in abnormal vasoreactivity, whereas maintenance of GLUT4 expression prevents hypertension-induced alteration in vascular reactivity (13).…”

Section: Systemic Hypertensionmentioning

confidence: 96%

Metabolism of vascular smooth muscle cells in vascular diseases

Shi

Yang

Cheng

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

196

120

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Vascular smooth muscle cells (VSMCs) are the fundamental component of the medial layer of arteries and are essential for arterial physiology and pathology. It is becoming increasingly clear that VSMCs can alter their metabolism to fulfill the bio-energetic and biosynthetic requirements. During vascular injury, VSMCs switch from a quiescent "contractile" phenotype to a highly migratory and proliferative "synthetic" phenotype. Recent studies find that the phenotype switching of VSMCs is driven by a metabolic switch. Metabolic pathways, including aerobic glycolysis, fatty acid oxidation, and amino acid metabolism, have distinct, indispensable roles in normal and dysfunctional vasculature. VSMCs metabolism is also related to the metabolism of endothelial cells. In the present review, we present a brief overview of VSMCs metabolism, and how it regulates the progression of several vascular diseases, including atherosclerosis, systemic hypertension, diabetes, pulmonary hypertension, vascular calcification, and aneurysms, and the effect of the risk factors for vascular disease (aging, cigarette smoking and excessive alcohol drinking) on VSMCs metabolism, to clarify the role of VSMCs metabolism in the key pathological process.

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“…We found that the expression of GLUT varied based on blood vessel size, which is in accord with the variable densities of VSMCs in different size vessels ( Craggs et al, 2015 ). Another recent report indicates that GLUT4 may act as one of the regulators of the tonic capacity of VSMCs ( Atkins et al, 2015 ), suggesting that in CADASIL the blood flow restriction might be, in part, due to reduced GLUT4 (and GLUT2).…”

Section: Discussionmentioning

confidence: 99%

Insulin-Independent and Dependent Glucose Transporters in Brain Mural Cells in CADASIL

et al. 2020

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Typical cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the human NOTCH3 gene. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small vessels. Blood regulating vascular smooth muscle cells (VSMCs) appear as the key target in CADASIL but the pathogenic mechanisms remain unclear. With the hypothesis that brain glucose metabolism is disrupted in VSMCs in CADASIL, we investigated post-mortem tissues and VSMCs derived from CADASIL patients to explore gene expression and protein immunoreactivity of glucose transporters (GLUTs), particularly GLUT4 and GLUT2 using quantitative RT-PCR and immunohistochemical techniques. In vitro cell model analysis indicated that both GLUT4 and -2 gene expression levels were down-regulated in VSMCs derived from CADASIL patients, compared to controls. In vitro studies further indicated that the down regulation of GLUT4 coincided with impaired glucose uptake in VSMCs, which could be partially rescued by insulin treatment. Our observations on reduction in GLUTs in VSMCs are consistent with previous findings of decreased cerebral blood flow and glucose uptake in CADASIL patients. That impaired ability of glucose uptake is rescued by insulin is also consistent with previously reported lower proliferation rates of VSMCs derived from CADASIL subjects. Overall, these observations are consistent with the development of severe cerebral arteriopathy in CADASIL, in which VSMCs are replaced by widespread fibrosis.

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Maintenance of GLUT4 expression in smooth muscle prevents hypertension-induced changes in vascular reactivity

Cited by 8 publications

References 31 publications

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Metabolism of vascular smooth muscle cells in vascular diseases

Insulin-Independent and Dependent Glucose Transporters in Brain Mural Cells in CADASIL

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