Vascular Actions of Angiotensin 1–7 in the Human Microcirculation

Durand, Matthew J.; Zinkevich, Natalya S.; Riedel, Michael; Gutterman, David D.; Nasci, Victoria; Salato, Valerie K.; Hijjawi, John B.; Reuben, Charles F.; North, Paula E.; Beyer, Andreas

doi:10.1161/atvbaha.116.307518

Cited by 55 publications

(51 citation statements)

References 60 publications

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“…These findings suggest that loss of TERT may be a key component of the pathophysiology of cardiovascular diseases affected by overabundance of microvascular ROS, which may precipitate proinflammatory changes, or impaired overall dilator capacity, which may lead to downstream ischemia. The data presented in this report are consistent with our earlier findings using short-term pharmacological TERT inhibition (2,9) and extend these initial observations to chronic and in vivo effects of TERT in a genetic model. Moreover, the observation that deletion of TERC does not contribute the microvascular phenotypes identified in early generations underlines the physiological relevance of TERT itself as an independent regulator of ROS generation and FMD.…”

Section: Discussionsupporting

confidence: 91%

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Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction

Ait‐Aissa

Kadlec

Hockenberry

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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A rise in reactive oxygen species (ROS) may contribute to cardiovascular disease by reducing nitric oxide (NO) levels, leading to loss of NO's vasodilator and anti-inflammatory effects. Although primarily studied in larger conduit arteries, excess ROS release and a corresponding loss of NO also occur in smaller resistance arteries of the microcirculation, but the underlying mechanisms and therapeutic targets have not been fully characterized. We examined whether either of the two subunits of telomerase, telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC), affect microvascular ROS production and peak vasodilation at baseline and in response to in vivo administration to angiotensin II (ANG II). We report that genetic loss of TERT [maximal dilation: 52.0 ± 6.1% with vehicle, 60.4 ± 12.9% with N-nitro-l-arginine methyl ester (l-NAME), and 32.2 ± 12.2% with polyethylene glycol-catalase (PEG-Cat) ( P < 0.05), means ± SD, n = 9-19] but not TERC [maximal dilation: 79 ± 5% with vehicle, 10.7 ± 9.8% with l-NAME ( P < 0.05), and 86.4 ± 8.4% with PEG-Cat, n = 4-7] promotes flow-induced ROS formation. Moreover, TERT knockout exacerbates the microvascular dysfunction resulting from in vivo ANG II treatment, whereas TERT overexpression is protective [maximal dilation: 88.22 ± 4.6% with vehicle vs. 74.0 ± 7.3% with ANG II (1,000 ng·kg·min) ( P = not significant), n = 4]. Therefore, loss of TERT but not TERC may be a key contributor to the elevated microvascular ROS levels and reduced peak dilation observed in several cardiovascular disease pathologies. NEW & NOTEWORTHY This study identifies telomerase reverse transcriptase (TERT) but not telomerase RNA component as a key factor regulating endothelium-dependent dilation in the microcirculation. Loss of TERT activity leads to microvascular dysfunction but not conduit vessel dysfunction in first-generation mice. In contrast, TERT is protective in the microcirculation in the presence of prolonged vascular stress. Understanding the mechanism of how TERT protects against vascular stress represents a novel target for the treatment of vascular disorders.

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Section: Discussionsupporting

confidence: 91%

“…Western blot analysis. Protein expression was analyzed as previously described (9). Briefly, total protein (30 g) from MA (6 -8 pooled arteries/mouse) lysates was loaded and separated using SDS-PAGE and then transferred into a polyvinylidene difluoride membrane.…”

Section: Methodsmentioning

confidence: 99%

Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction

Ait‐Aissa

Kadlec

Hockenberry

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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“…21 Mechanistically, ceramide-induced reduction in telomerase activity in mitochondria has been shown to cause this switch. 22,23 Although the sources and regulatory mechanisms of physiological ROS are inconclusive, local subcellular concentrations at microdomains rather than net intracellular concentrations may be critical to determine whether the effects of ROS can be gainful or harmful to cellular processes, and colocalization of the source and target of ROS may help prevent nonspecific injurious oxidations. 24 Among redox regulating proteins, endothelial thioredoxin reductase 2 has been shown to play a key role in the maintenance of healthy endothelial functions, 25 and peroxisome proliferator receptor-γ coactivator 1α has emerged as a master regulator of endothelial functions, including protection against oxidative stress, inflammation, and atherosclerosis.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Endothelial Functions

Godo

Shimokawa

2017

ATVB

376

258

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e108T he endothelium plays important roles in modulating vascular tone by synthesizing and releasing an array of endothelium-derived relaxing factors, including vasodilator prostaglandins, NO, and endothelium-dependent hyperpolarization (EDH) factors, as well as endothelium-derived contracting factors.1,2 Such redundant mechanisms, like endogenous hyperglycemic hormones, are advantageous for ensuring proper maintenance of vascular tone under pathological conditions, where one of the vasoactive factor-mediated responses is compromised favoring a vasoconstrictor, prothrombotic, and proinflammatory state. Endothelial dysfunction is mainly caused by reduced production or action of endothelium-derived relaxing factors and could be an initial step toward cardiovascular disease.1 Indeed, evaluation of endothelial functions in humans has attracted much attention in the clinical settings because it serves as an excellent surrogate marker of cardiovascular events. For instance, endothelial dysfunction, as evaluated by impaired flow-mediated dilation of the brachial artery or digital reactive hyperemia index in peripheral arterial tonometry, is associated with future cardiovascular events in patients with coronary artery disease, 3-5 and 1-SD decrease in flow-mediated dilation or reactive hyperemia index is associated with doubling of cardiovascular event risk. 6 These observations suggest that endothelial function in peripheral vascular beds could predict future cardiovascular events.In this review, we will sum up the current advances and trends in the research on endothelial functions from bench to bedside with particular focus on recent publications in Arteriosclerosis, Thrombosis, and Vascular Biology. Earlier highlights of the journal on endothelial biology are extensively summarized in some review articles. 7-9 Emerging Modulators of Endothelial Functions Shear StressAs Lüscher and Corti 10 described in an editorial, flow is the signal of life. This physical force is sensed by the endothelium lining internal surface of the whole cardiovascular system to be translated into numerous downstream signaling pathways in a moment to moment manner in response to diverse physiological demands in the body. Indeed, shear stress is one of the important physiological cues that make endothelial cells synthesize and release endothelium-derived relaxing factors to cause relaxation of underlying vascular smooth muscle and vasodilatation. In this context, novel mechanisms of endothelial mechanotransduction in health and disease have been unveiled and summarized in a review series published recently in Arteriosclerosis, Thrombosis, and Vascular Biology. 11,12 Briefly, Zhou et al 12 emphasized the distinct roles of atheroprotective laminar or pulsatile shear stress versus atheroprone oscillatory shear stress or disturbed flow and discussed in detail the underlying molecular mechanisms that are dependent on these patterns of flow. Abe and Berk 11 further reviewed the current knowledge on the dual roles of shear stress with emphasis plac...

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“…In cultured endothelial cells, stimulation of PPARγ with pioglitazone (TZD) improve endothelial stress resistance and reduces susceptibility to senescence stimuli by activating telomerase and reducing senescence marker expression (Table 2) (89). Recent data by Durand et al (90) (supplemental material) further support this notion, as Rosiglitazone restored normal NO mediated, endothelium-dependent dilation in vessels from subjects with CAD (normally mediated by H 2 O 2 ) in a telomerase-dependent manner. The underlying mechanisms determining how PPARγ differentially regulates TERT, dependent on cell type, has yet to be determined.…”

Section: Role Of Telomerase In Of Cardiovascular Diseasementioning

confidence: 81%

Friend or foe? Telomerase as a pharmacological target in cancer and cardiovascular disease

Ait‐Aissa

Ebben

Kadlec

et al. 2016

Pharmacological Research

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Aging, cancer, and chronic disease have remained at the forefront of basic biological research for decades. Within this context, significant attention has been paid to the role of telomerase, the enzyme responsible for lengthening telomeres, the nucleotide sequences located at the end of chromosomes found in the nucleus. Alterations in telomere length and telomerase activity are a common denominator to the underlying pathology of these diseases. While nuclear-specific, telomere-lengthening effects of telomerase impact cellular/organismal aging and cancer development, non-canonical, extra-nuclear, and non-telomere-lengthening contributions of telomerase have only recently been described and their exact physiological implications are ill defined. Although the mechanism remains unclear, recent reports reveal that the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), regulates levels of mitochondrial-derived reactive oxygen species (mtROS), independent of its established role in the nucleus. Telomerase inhibition has been the target of chemotherapy (directed or indirectly) for over a decade now, yet no telomerase inhibitor is FDA approved and few are currently in late-stage clinical trials, possibly due to underappreciation of the distinct extra-nuclear functions of telomerase. Moreover, evaluation of telomerase-specific therapies is largely limited to the context of chemotherapy, despite reports of the beneficial effects of telomerase activation in the cardiovascular system in relation to such processes as endothelial dysfunction and myocardial infarction. Thus, there is a need for better understanding of telomerase-focused cell and organism physiology, as well as development of telomerase-specific therapies in relation to cancer and extension of these therapies to cardiovascular pathologies. This review will detail findings related to telomerase and evaluate its potential to serve as a therapeutic target.

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Vascular Actions of Angiotensin 1–7 in the Human Microcirculation

Cited by 55 publications

References 60 publications

Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction

Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction

Endothelial Functions

Friend or foe? Telomerase as a pharmacological target in cancer and cardiovascular disease

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