Reduced deformability contributes to impaired deoxygenation‐induced ATP release from red blood cells of older adult humans

Racine, Matthew L.; Dinenno, Frank A.

doi:10.1113/jp278338

Cited by 29 publications

(31 citation statements)

References 93 publications

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“…Red blood cell distribution has been identified as a biomarker for predicting mortality, response to treatment and incidence of heart failure in patients with PH [ 187 , 188 ]. Increased pulmonary vascular resistance is associated with red blood cell stiffness in mice and ROCK regulates the level of abnormal erythrocyte [ 189 , 190 ]. Red blood cells from PH patients were found to have increased ROCK content, which was also correlated to their lower endothelial NOS activity, because treatment with fasudil recovered the NO production [ 191 , 192 ].…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

“…Red blood cells from PH patients were found to have increased ROCK content, which was also correlated to their lower endothelial NOS activity, because treatment with fasudil recovered the NO production [ 191 , 192 ]. ROCK may reduce ATP release from human erythrocytes under hypoxic conditions [ 190 ], thus impairing the purinergic stimulation of endothelium-dependent vasodilator responses and favoring hypoxic pulmonary vasoconstriction.…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

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ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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Pulmonary hypertension (PH) is a cardiovascular disease caused by extensive vascular remodeling in the lungs, which ultimately leads to death in consequence of right ventricle (RV) failure. While current drugs for PH therapy address the sustained vasoconstriction, no agent effectively targets vascular cell proliferation and tissue inflammation. Rho-associated protein kinases (ROCKs) emerged in the last few decades as promising targets for PH therapy, since ROCK inhibitors demonstrated significant anti-remodeling and anti-inflammatory effects. In this review, current aspects of ROCK inhibition therapy are discussed in relation to the treatment of PH and RV dysfunction, from cell biology to preclinical and clinical studies.

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Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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“…Therefore, strategies aimed at improving ATP availability in vivo may be effective for improving functional sympatholysis in older adults. More specifically, the red blood cell is a particularly attractive therapeutic target because it is the primary source of intravascular ATP during exercise (Kirby et al 2013), and ageing is associated with impaired erythrocyte-mediated ATP release (Kirby et al 2012) as a result of reduced cell deformability (Racine & Dinenno, 2019). Therefore, improving erythrocyte-mediated ATP release in response to deoxygenation (possibly via rho-kinase inhibition) would provide a targeted approach for improving vasodilatory and sympatholytic signalling in tissues where metabolic demand is highest.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Augmentation of endothelium‐dependent vasodilatory signalling improves functional sympatholysis in contracting muscle of older adults

Hearon

Richards

Racine

et al. 2020

The Journal of Physiology

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Key points The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical for maintaining blood flow during exercise‐mediated sympathoexcitation. Functional sympatholysis and endothelial function are impaired with ageing, resulting in compromised blood flow and oxygen delivery to contracting skeletal muscle during exercise. In the present study, intra‐arterial infusion of ACh or ATP to augment endothelium‐dependent signalling during exercise attenuated α1‐adrenergic vasoconstriction in the contracting muscle of older adults. The vascular signalling mechanisms capable of functional sympatholysis are preserved in healthy ageing, and thus the age‐related impairment in functional sympatholysis probably results from the loss of a functional signal (e.g. plasma [ATP]) as opposed to an intrinsic endothelial dysfunction. Abstract The ability of contracting skeletal muscle to attenuate sympathetic α‐adrenergic vasoconstriction (‘functional sympatholysis’) is impaired with age. In young adults, increasing endothelium‐dependent vasodilatory signalling during mild exercise augments sympatholysis. In the present study, we tested the hypothesis that increasing endothelium‐dependent signalling during exercise in older adults can improve sympatholysis. In 16 older individuals (Protocol 1, n = 8; Protocol 2, n = 8), we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra‐arterial infusion of phenylephrine (PE; α1‐agonist) during (i) infusion of an endothelium‐dependent vasodilator alone (Protocol 1: ACh or Protocol 2: low dose ATP); (ii) mild handgrip exercise (5% maximum voluntary contraction; MVC); (iii) moderate handgrip exercise (15% MVC); and (iv) mild or moderate handgrip exercise + infusion of ACh or ATP to augment endothelium‐dependent signalling. PE caused robust vasoconstriction in resting skeletal muscle during control vasodilator infusions (ΔFVC: ACh: −31 ± 3 and ATP: −30 ± 4%). PE‐mediated vasoconstriction was not attenuated by mild or moderate intensity exercise (ΔFVC: 5% MVC: −30 ± 9; 15% MVC: −33 ± 8%; P > 0.05 vs. control ACh and ATP), indicative of impaired sympatholysis, and ACh or ATP infusion during mild exercise did not impact this response. However, augmentation of endothelium‐dependent signalling via infusion of ACh or ATP during moderate intensity exercise attenuated PE‐mediated vasoconstriction (ΔFVC: −13 ± 1 and −19 ± 5%, respectively; P < 0.05 vs. all conditions). Our findings demonstrate that, given a sufficient stimulus, endothelium‐dependent sympatholysis remains intact in older adults. Strategies aimed at activating such pathways represent a viable approach for improving sympatholysis and thus tissue blood flow and oxygen delivery in older adults.

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“…Mouse erythrocytes were isolated and re-suspended as previously described (29). Whole blood was collected via cardiac puncture in heparinized tubes, centrifuged at 500 x g for 10 minutes at 4°C.…”

Section: Isolation Of Mouse Erythrocytesmentioning

confidence: 99%

Skeletal muscle tissue secretes more extracellular vesicles than white adipose tissue and myofibers are a major source ex vivo but not in vivo

Estrada

Valenti

Hehn

et al. 2020

Preprint

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Circulating extracellular vesicles (EVs) are biomarkers of and contributors to the etiology of disease. Skeletal muscle (SkM) and white adipose tissue (WAT) are the two largest organs by mass in humans and rodents but the relative contribution of EVs from these tissues is unknown. We hypothesized that SkM tissue secretes more EVs than WAT and that a dual fluorescent reporter mouse could be used to detect SkM myofiber-derived EVs in vivo. Human Protein Atlas data and directly measuring EV secretion in mouse SkM and WAT using an ex vivo tissue explant model confirmed that SkM tissue secretes more EVs than WAT. Differences in EV secretion between SkM and WAT were not due to SkM contraction but may be explained by differences in tissue metabolic capacity. A SkM myofiber-specific dual fluorescent reporter mouse was created. Spectral flow cytometry revealed that SkM myofibers are a major source of SkM tissue-derived EVs ex vivo but few reach the circulation in vivo. Our findings demonstrate that SkM secretes more EVs than WAT and many come from SkM myofibers, but our in vivo data indicate that EVs secreted by SkM myofibers may remain primarily in their local extracellular environment.

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Reduced deformability contributes to impaired deoxygenation‐induced ATP release from red blood cells of older adult humans

Cited by 29 publications

References 93 publications

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Augmentation of endothelium‐dependent vasodilatory signalling improves functional sympatholysis in contracting muscle of older adults

Skeletal muscle tissue secretes more extracellular vesicles than white adipose tissue and myofibers are a major source ex vivo but not in vivo

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