Endothelial cell senescence in aging-related vascular dysfunction

Jia, Guanghong; Aroor, Annayya R.; Jia, Cassie; Sowers, James R.

doi:10.1016/j.bbadis.2018.08.008

Cited by 287 publications

(237 citation statements)

References 94 publications

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“…To estimate the FMD stimulus, shear rate area-under-the-curve (AUC) up to 40 s (Shear AUC) after cuff release was calculated. 28 Shear rate (s − 1 ) was calculated as 4 * mean velocity/diameter, and oscillatory index as retrograde shear rate/(antegrade shear rate + retrograde shear) * 100. 29 …”

Section: Methodsmentioning

confidence: 99%

“…Vascular homeostasis, and therefore cardiovascular disease risk, is partly governed by the vascular endothelium. 1 , 2 The gold-standard noninvasive approach for assessing endothelial function is the ultrasound-based flow-mediated dilation (FMD) test. 3 , 4 The FMD test measures an artery’s vasodilatory response to increased shear stress, where increased shear stress is induced by reactive hyperemia following 5 min of downstream ischemia.…”

Section: Introductionmentioning

confidence: 99%

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Endothelium function dependence of acute changes in pulse wave velocity and flow-mediated slowing

et al. 2020

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Flow-mediated slowing (FMS), defined as the minimum pulse wave velocity (PWVmin) during reactive hyperemia, is potentially a simple, user-objective test for examining endothelial function. The purpose of the current study was to determine the effects of a known endothelial dysfunction protocol on arm PWV and PWVmin. Complete data were successfully collected in 22 out of 23 healthy adults (23.8 years [SD 4.1], 16 F, 22.8 kg/m2 [SD 2.8]). Local endothelial dysfunction was induced by increasing retrograde shear stress in the upper arm, through inflation of a distal (forearm) tourniquet to 75 mmHg, for 30 min. Pre- and post-endothelial dysfunction, PWV was measured followed by simultaneous assessment of PWVmin and flow-mediated dilation (FMD). PWV was measured between the upper arm and wrist using an oscillometric device, and brachial FMD using ultrasound. FMD (%) and PWVmin (m/s) were calculated as the maximum increase in diameter and minimum PWV during reactive hyperemia, respectively. Endothelial dysfunction resulted in a large effect size (ES) decrease in FMD (∆ = −3.10%; 95% CI: –4.15, –2.05; ES = −1.3), and a moderate increase in PWV (∆ = 0.38 m/s; 95% CI: 0.07, 0.69; ES = 0.5) and PWVmin (∆ = 0.16 m/s; 95% CI: 0.05, 0.28; ES = 0.6). There was a large intra-individual (pre- vs post-endothelial dysfunction) association between FMD and PWVmin ( r = −0.61; 95% CI: –0.82, –0.24). In conclusion, acute change in PWV and PWVmin are at least partially driven by changes in endothelial function.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endothelium function dependence of acute changes in pulse wave velocity and flow-mediated slowing

et al. 2020

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“…4,8,[11][12][13][14][15][16] a-Klotho is often referred to as an ''anti-aging protein.'' 3,6,17,18 When overexpressed in mice, Klotho extends life (20-30%), reduces oxidative stress (OS), and demonstrates other prosurvival properties. [19][20][21][22][23][24][25] The potential of extending these results to humans has captured pharmaceutical interest in developing Klotho-based therapeutics to hinder the degenerative illnesses of aging.…”

Section: Introductionmentioning

confidence: 99%

“…135 Klotho as an Obligatory Co-receptor High concentrations of phosphate in the body are found in bone, teeth, and dental enamel as calcium phosphate crystals. 136,137 Klotho regulates phosphorus and calcium homeostasis 5,6,18,23,138 and functions as an obligatory co-receptor that binds and activates its related endocrine fibroblast growth factor (FGF) receptors (FGFRs) to potentiate its biological activities. 5,6,23,102,[139][140][141][142][143][144][145][146] FGFs are exemplary pleiotropic hormones that play numerous roles in cellular and metabolic homeostasis.…”

Section: Introductionmentioning

confidence: 99%

“…Klotho Structure, Distribution, and Function in MS Klotho is a single-pass transmembrane protein expressed in the brain (hippocampus and choroid plexus), kidney, eye (retina, optic nerve, lens) and parathyroid gland, and less so in other tissues. 3,18,27,102,183,184 A soluble form of Klotho (sKlotho), primarily secreted from the kidney, circulates in blood, urine, and cerebrospinal fluid, exerting different biological effects in multiple tissues as a humoral factor. 5,6,8,52,[185][186][187][188][189] In the eye, Klotho protects against OS 53,55,58,153,190,191 and is essential to the proper maintenance and function of the ocular system, 12,26,[192][193][194][195] being expressed throughout the retina, with the highest levels in retinal ganglion cells.…”

Section: Introductionmentioning

confidence: 99%

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Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

Moos

Faller

Glavas

et al. 2020

BioResearch Open Access

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In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.

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Direct administration of mesenchymal stem cell‐derived mitochondria improves cardiac function after infarction via ameliorating endothelial senescence

Liang

Zhang

Lin

et al. 2022

Bioengineering & Transla Med

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Mitochondrial dysfunction is considered to be a key contributor to the development of heart failure. Replacing injured mitochondria with healthy mitochondria to restore mitochondrial bioenergy in myocardium holds great promise for cardioprotection after infarction. This study aimed to investigate whether direct transplantation of exogenous mitochondria derived from mesenchymal stem cells (MSC‐mt) is beneficial and superior in protecting cardiac function in a mouse model of myocardial infarction (MI) compared to mitochondria derived from skin fibroblast (FB‐mt) and to explore the underlying mechanisms from their effects on the endothelial cells. The isolated MSC‐mt presented intact mitochondrial morphology and activity, as determined by electron microscopy, JC‐1 mitochondrial membrane potential assay, and seahorse assay. Direct injection of MSC‐mt into the peri‐infarct region in a mouse MI model enhanced blood vessel density, inhibited cardiac remodeling and apoptosis, thus improving heart function compared with FB‐mt group. The injected MSC‐mt can be tracked in the endothelial cells. In vitro, the fluorescence signal of MSC‐mt can be detected in human umbilical vein endothelial cells (HUVECs) by confocal microscopy and flow cytometry after coculture. Compared to FB‐mt, MSC‐mt more effectively protected the HUVECs from oxidative stress‐induced apoptosis and reduced mitochondrial production of reactive oxygen species. MSC‐mt presented superior capacity in inducing tube formation, enhancing SCF secretion, ATP content and cell proliferation in HUVECs compared to FB‐mt. Mechanistically, MSC‐mt administration alleviated oxidative stress‐induced endothelial senescence via activation of ERK pathway. These findings suggest that using MSCs as sources of mitochondria is feasible and that proangiogenesis could be the mechanism by which MSC‐mt transplantation attenuates MI. MSC‐mt transplantation might serve as a new therapeutic strategy for treating MI.

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Endothelial cell senescence in aging-related vascular dysfunction

Cited by 287 publications

References 94 publications

Endothelium function dependence of acute changes in pulse wave velocity and flow-mediated slowing

Endothelium function dependence of acute changes in pulse wave velocity and flow-mediated slowing

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

Direct administration of mesenchymal stem cell‐derived mitochondria improves cardiac function after infarction via ameliorating endothelial senescence

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