Premature death and age-related cardiac dysfunction in male eNOS-knockout mice

Li, Wei; Mital, Seema; Ojaimi, Caroline; Csiszár, Anna; Kaley, Gabor; Hintze, Thomas H.

doi:10.1016/j.yjmcc.2004.05.005

Cited by 80 publications

(69 citation statements)

References 42 publications

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“…11 If overactive, however, it plays a role in a variety of pathologies. 12 Although heart defects have been found in some studies of eNOS knockout mice, 13,14 the histological features of the kidneys when examined were deemed unremarkable. 6 In contrast, our observations have revealed focal progressive kidney lesions in the majority of animals examined.…”

Section: Discussionmentioning

confidence: 99%

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Forbes

Thornhill

Park

et al. 2007

The American Journal of Pathology

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Because endothelial nitric-oxide synthase (eNOS) is generally considered protective against renal injury , we examined eNOS knockout mice for kidney pathology. In 80% of the adults examined , the renal surface was marked by distinct indented scars containing crowded small glomeruli but lacking attached tubules. Although vasculature was intact in the scars , Bowman's space was dilated and glomerular tufts were degenerated. The atubular glomeruli were embedded in a dense interstitial matrix composed of cells positive for fibroblast (FSP-1) or macrophage (F4/80) markers , degenerated proximal tubules and collecting ducts , and diffuse fibrotic deposits. Surrounding regions of kidney contained mostly normal-appearing tubules , but enlarged or sclerotic glomeruli were also present. In neonatal animals , apoptosis and necrosis were concentrated in tubules within focal parenchymal zones , with narrowing of the glomerulotubular "neck." In summary , targeted deletion of eNOS in mice leads to progressive focal renal abnormalities , including glomerular hypoplasia , and tubular cell death , leading to separation of glomeruli from tubules and tubular disruption. These abnormalities begin developing during the normal up-regulation of eNOS in the maturing kidney and are similar to those of a variety of chronic renal disorders. Endogenous renal eNOS production therefore seems critical for the maintenance of nephron maturation and integrity. Endothelial nitric-oxide synthase (eNOS) is implicated in numerous aspects of renal vascular control and function. It is thought to exert a vasculoprotective effect by modulation of kidney blood flow through counterbalancing the effects of the renin-angiotensin system.1 Following NOS inhibition, the activity of the renin-angiotensin system is increased, with increased expression of fibronectin and ␣-smooth muscle actin. 2 Either angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists ameliorate the consequent renal injury.2 In contrast, ischemic preconditioning increases renal eNOS protein expression and suppresses ischemic injury.3 As its name implies, eNOS is located within the renal vascular endothelium in the adult. However, recent findings indicate that, in neonatal rats, this enzyme is also transiently present in proximal tubules, 4 whereas eNOS mRNA is present in the inner medullary collecting duct in the adult.

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Section: Discussionmentioning

confidence: 99%

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Forbes

Thornhill

Park

et al. 2007

The American Journal of Pathology

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“…In blood vessels, the cell membrane-associated NAD(P)H oxidase is a significant source of ROS production, and an increased vascular NAD(P)H oxidase has been shown to contribute importantly to the symptoms of vascular aging, including increased O 2 Ϫ ⅐ production, decreased bioavailability of the vasodilator and anti-apoptotic NO (1,12,13,15,19,24,37), increased cardiac oxygen demand (1), and vascular inflammation (Ungvari Z, unpublished observation). EB fluorescence measurements revealed that both the endothelial and smooth muscle cells of NMR vessels produce O 2 Ϫ ⅐ (Fig.…”

Section: Discussionmentioning

confidence: 99%

Comparison of endothelial function, O₂⁻· and H₂O₂ production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice

Labinskyy

Csiszár

Orosz

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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vari. Comparison of endothelial function, O 2Ϫ ⅐ and H2O2 production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice. Am J Physiol Heart Circ Physiol 291: H2698 -H2704, 2006; doi:10.1152/ajpheart.00534.2006.-Vascular aging is characterized by decreased nitric oxide (NO) bioavailability, oxidative stress, and enhanced apoptotic cell death. We hypothesized that interspecies comparative assesment of vascular function among rodents with disparate longevity may offer insight into the mechanisms determining successful vascular aging. We focused on four rodents that show approximately an order of magnitude range in maximum longevity (ML). The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known (ML Ͼ 28 yr), Damara mole rats (DMRs, Cryptomys damarensis; ML ϳ 16 yr) and guinea pigs (GPs, Cavia porcellus; ML ϳ 6 yr) have intermediate longevity, whereas laboratory mice are short living (ML ϳ 3.5 yr). We compared interspecies differences in endothelial function, O 2 Ϫ ⅐ and H2O2 production, and resistance to apoptotic stimuli in blood vessels. Sensitivity to acetylcholine-induced, NO-mediated relaxation was smaller in carotid arteries from NMRs, GPs, and DMRs than in mouse vessels. Measurements of production of O 2 Ϫ ⅐ (lucigenin chemiluminescence and ethidium bromide fluorescence) and H2O2 (dichlorofluorescein fluorescence) showed that free radical production in vascular endothelial and smooth muscle cells is comparable in vessels of the three longer-living species and in arteries of shorter-living mice. In mouse arteries, H2O2 (from 10 Ϫ6 to 10 Ϫ3 mol/l) and heat exposure (42°C for 15-45 min) enhanced apoptotic cell death, as indicated by an increased DNA fragmentation rate and increased caspase 3/7 activity. In NMR vessels, only the highest doses of H2O2 enhanced apoptotic cell death, whereas heat exposure did not increase DNA fragmentation rate. Interspecies comparison showed there is a negative correlation between H2O2-induced apoptotic cell death and ML. Thus endothelial vasodilator function and vascular production of reactive oxygen species do not correlate with maximal lifespan, whereas increased lifespan potential is associated with an increased vascular resistance to proapoptotic stimuli. senescence; comparative biology; vascular disease; atherosclerosis; IN THE UNITED STATES, the number of persons aged Ն65 years is expected to increase from ϳ35 million in 2000 to an estimated 71 million in 2030 (according to the Center for Disease Control). Epidemiological studies suggest that aging of the vascular system is directly responsible for Ͼ50% of mortality and morbidity in these age groups. Despite the growing incidence of aging-induced coronary artery disease, stroke, and diabetic vasculopathy, the factors determining successful vascular aging are still poorly understood.Vascular aging is characterized by proatherogenic functional and phenotypic alterations, including impaired endothelial nitric oxide (NO) mediation, increased product...

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“…In separate experiments aortic segments of eNOS Ϫ/Ϫ and wild-type control mice (Jackson Laboratories, Bar Harbor, ME) (22) were maintained in organoid culture under sterile conditions in F12 medium (Gibco) containing antibiotics (100 UI/l penicillin, 100 mg/l streptomycin, and 10 g/l fungizone) and supplemented with 5% FCS (Boehringer-Mannheim) as previously described (39) in the presence or absence of resveratrol (10 Ϫ5 mol/l, for 24 h). After the culture period expression of mitochondrial biogenesis factors was assessed by QRT-PCR.…”

Section: ϫ4mentioning

confidence: 99%

Resveratrol induces mitochondrial biogenesis in endothelial cells

Csiszár

Labinskyy

Pinto

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Pathways that regulate mitochondrial biogenesis are potential therapeutic targets for the amelioration of endothelial dysfunction and vascular disease. Resveratrol was shown to impact mitochondrial function in skeletal muscle and the liver, but its role in mitochondrial biogenesis in endothelial cells remains poorly defined. The present study determined whether resveratrol induces mitochondrial biogenesis in cultured human coronary arterial endothelial cells (CAECs). In CAECs resveratrol increased mitochondrial mass and mitochondrial DNA content, upregulated protein expression of electron transport chain constituents, and induced mitochondrial biogenesis factors (proliferator-activated receptor-coactivator-1α, nuclear respiratory factor-1, mitochondrial transcription factor A). Sirtuin 1 (SIRT1) was induced, and endothelial nitric oxide (NO) synthase (eNOS) was upregulated in a SIRT1-dependent manner. Knockdown of SIRT1 (small interfering RNA) or inhibition of NO synthesis prevented resveratrol-induced mitochondrial biogenesis. In aortas of type 2 diabetic (db/db) mice impaired mitochondrial biogenesis was normalized by chronic resveratrol treatment, showing the in vivo relevance of our findings. Resveratrol increases mitochondrial content in endothelial cells via activating SIRT1. We propose that SIRT1, via a pathway that involves the upregulation of eNOS, induces mitochondrial biogenesis. Resveratrol induced mitochondrial biogenesis in the aortas of type 2 diabetic mice, suggesting the potential for new treatment approaches targeting endothelial mitochondria in metabolic diseases.

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Premature death and age-related cardiac dysfunction in male eNOS-knockout mice

Cited by 80 publications

References 42 publications

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Comparison of endothelial function, O₂⁻· and H₂O₂ production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice

Resveratrol induces mitochondrial biogenesis in endothelial cells

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Premature death and age-related cardiac dysfunction in male eNOS-knockout mice

Cited by 80 publications

References 42 publications

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Comparison of endothelial function, O2−· and H2O2 production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice

Resveratrol induces mitochondrial biogenesis in endothelial cells

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Comparison of endothelial function, O₂⁻· and H₂O₂ production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice