Skeletal muscle expression of adipose-specific phospholipase in peripheral artery disease

2020 ◽  
Vol 25 (5) ◽  
pp. 401-410
Author(s):  
Caitlin Parmer ◽  
Ana Luisa De Sousa-Coelho ◽  
Henry S Cheng ◽  
Grace Daher ◽  
Alison Burkart ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Peripheral Artery Disease ◽  
Muscle Metabolism ◽  
Diabetic Mice ◽  
Peripheral Artery ◽  
Artery Ligation ◽  
Muscle Gene Expression ◽  
Walking Capacity ◽  
Artery Disease

Flow-limiting atherosclerotic lesions of arteries supplying the limbs are a cause of symptoms in patients with peripheral artery disease (PAD). Musculoskeletal metabolic factors also contribute to the pathophysiology of claudication, which is manifest as leg discomfort that impairs walking capacity. Accordingly, we conducted a case–control study to determine whether skeletal muscle metabolic gene expression is altered in PAD. Calf skeletal muscle gene expression of patients with PAD and healthy subjects was analyzed using microarrays. The top-ranking gene differentially expressed between PAD and controls (FDR < 0.001) was PLA2G16, which encodes adipose-specific phospholipase A2 (AdPLA) and is implicated in the maintenance of insulin sensitivity and regulation of lipid metabolism. Differential expression was confirmed by qRT-PCR; PLA2G16 was downregulated by 68% in patients with PAD ( p < 0.001). Expression of Pla2g16 was then measured in control (db/+) and diabetic (db/db) mice that underwent unilateral femoral artery ligation. There was significantly reduced expression of Pla2g16 in the ischemic leg of both control and diabetic mice (by 51%), with significantly greater magnitude of reduction in the diabetic mice (by 79%). We conclude that AdPLA is downregulated in humans with PAD and in mice with hindlimb ischemia. Reduced AdPLA may contribute to impaired walking capacity in patients with PAD via its effects on skeletal muscle metabolism. Further studies are needed to fully characterize the role of AdPLA in PAD and to investigate its potential as a therapeutic target for alleviating symptoms of claudication.

scholarly journals Investigation of the mechanisms of cyclooxygenase-mediated mechanoreflex sensitization in a rat model of simulated peripheral artery disease

2019 ◽  
Vol 317 (5) ◽  
pp. H1050-H1061 ◽  
Author(s):  
Alec L. E. Butenas ◽  
Tyler D. Hopkins ◽  
Korynne S. Rollins ◽  
Kennedy P. Felice ◽  
Steven W. Copp
Keyword(s):  
Skeletal Muscle ◽  
Peripheral Artery Disease ◽  
Femoral Artery ◽  
Skeletal Muscles ◽  
Pressor Response ◽  
Peripheral Artery ◽  
Artery Ligation ◽  
Exercise Pressor Reflex ◽  
Pressor Reflex ◽  
Artery Disease

Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the exercise pressor reflex, is exaggerated in patients with peripheral artery disease (PAD) and in a rat PAD model with a chronically ligated femoral artery. The cyclooxygenase (COX) pathway contributes to the exaggerated pressor response during rhythmic skeletal muscle contractions in patients with PAD, but the specific mechanism(s) of the COX-mediated exaggeration are not known. In decerebrate, unanesthetized rats with a chronically ligated femoral artery (“ligated” rats), we hypothesized that hindlimb arterial injection of the COX inhibitor indomethacin would reduce the pressor response during 1-Hz dynamic hindlimb skeletal muscle stretch; a model of the activation of the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). In ligated rats ( n = 7), indomethacin reduced the pressor response during stretch (control: 30 ± 4; indomethacin: 12 ± 3 mmHg; P < 0.01), whereas there was no effect in rats with “freely perfused” femoral arteries ( n = 6, control: 18 ± 5; indomethacin: 17 ± 5 mmHg; P = 0.87). In ligated rats ( n = 4), systemic indomethacin injection had no effect on the pressor response during stretch. Femoral artery ligation had no effect on skeletal muscle COX protein expression or activity or concentration of the COX metabolite prostaglandin E2. Conversely, femoral artery ligation increased expression of the COX metabolite receptors endoperoxide 4 and thromboxane A2-R in dorsal root ganglia tissue. We conclude that, in ligated rats, the COX pathway sensitizes the peripheral endings of mechanoreflex afferents, which occurs principally as a result of increased expression of COX metabolite receptors. NEW & NOTEWORTHY We demonstrate that the mechanoreflex is sensitized by the cyclooxygenase (COX) pathway within hindlimb skeletal muscles in the rat chronic femoral artery ligation model of simulated peripheral artery disease (PAD). The mechanism of sensitization appears attributable to increased receptors for COX metabolites on sensory neurons and not increased concentration of COX metabolites. Our data may carry important clinical implications for patients with PAD who demonstrate exaggerated increases in blood pressure during exercise compared with healthy counterparts.

Loss of Id3 (Inhibitor of Differentiation 3) Increases the Number of IgM-Producing B-1b Cells in Ischemic Skeletal Muscle Impairing Blood Flow Recovery During Hindlimb Ischemia

2021 ◽  
Author(s):  
Victoria Osinski ◽  
Prasad Srikakulapu ◽  
Young Min Haider ◽  
Melissa A. Marshall ◽  
Vijay C. Ganta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
B Cell ◽  
Peripheral Artery Disease ◽  
Myeloid Cell ◽  
Hindlimb Ischemia ◽  
Peripheral Artery ◽  
Artery Ligation ◽  
Artery Disease

Objective: Neovascularization can maintain and even improve tissue perfusion in the setting of limb ischemia during peripheral artery disease. The molecular and cellular mechanisms mediating this process are incompletely understood. We investigate the potential role(s) for Id3 (inhibitor of differentiation 3) in regulating blood flow in a murine model of hindlimb ischemia (HLI). Approach and Results: HLI was modeled through femoral artery ligation and resection and blood flow recovery was quantified by laser Doppler perfusion imaging. Mice with global Id3 deletion had significantly impaired perfusion recovery at 14 and 21 days of HLI. Endothelial- or myeloid cell-specific deletion of Id3 revealed no effect on perfusion recovery while B-cell–specific knockout of Id3 (Id3 BKO ) revealed a significant attenuation of perfusion recovery. Flow cytometry revealed no differences in ischemia-induced T cells or myeloid cell numbers at 7 days of HLI, yet there was a significant increase in B-1b cells in Id3 BKO . Consistent with these findings, ELISA demonstrated increases in skeletal muscle and plasma IgM. In vitro experiments demonstrated reduced proliferation and increased cell death when endothelial cells were treated with conditioned media from IgM-producing B-1b cells and tibialis anterior muscles in Id3 BKO mice showed reduced density of total CD31 + and αSMA + CD31 + vessels. Conclusions: This study is the first to demonstrate a role for B-cell–specific Id3 in maintaining blood flow recovery during HLI. Results suggest a role for Id3 in promoting blood flow during HLI and limiting IgM-expressing B-1b cell expansion. These findings present new mechanisms to investigate in peripheral artery disease pathogenesis.

scholarly journals Leg heat therapy improves perceived physical function but does not enhance walking capacity or vascular function in patients with peripheral artery disease

2020 ◽  
Vol 129 (6) ◽  
pp. 1279-1289
Author(s):  
Jacob C. Monroe ◽  
Chen Lin ◽  
Susan M. Perkins ◽  
Yan Han ◽  
Brett J. Wong ◽  
...  
Keyword(s):  
Physical Function ◽  
Peripheral Artery Disease ◽  
Vascular Function ◽  
Controlled Study ◽  
Peripheral Artery ◽  
Walking Capacity ◽  
Heat Therapy ◽  
Walking Performance ◽  
Artery Disease ◽  
Potent Vasoconstrictor

This is the first sham-controlled study to investigate the effects of leg heat therapy (HT) on walking performance, vascular function, and quality of life in patients with peripheral artery disease (PAD). Adherence to HT was high, and the treatment was well tolerated. Our findings revealed that HT applied with water-circulating trousers evokes a clinically meaningful increase in perceived physical function and reduces the serum concentration of the potent vasoconstrictor endothelin-1 in patients with PAD.

scholarly journals Skeletal muscle capillary density is related to anaerobic threshold and claudication in peripheral artery disease

2020 ◽  
Vol 25 (5) ◽  
pp. 411-418
Author(s):  
Brian D Duscha ◽  
William E Kraus ◽  
William S Jones ◽  
Jennifer L Robbins ◽  
Lucy W Piner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Peripheral Artery Disease ◽  
Anaerobic Threshold ◽  
Cardiopulmonary Exercise Testing ◽  
Capillary Density ◽  
Exercise Intolerance ◽  
Peripheral Artery ◽  
Cross Sectional ◽  
Control Subjects ◽  
Artery Disease

Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, causing claudication and exercise intolerance. Exercise intolerance may result from reduced skeletal muscle capillary density and impaired muscle oxygen delivery. This cross-sectional study tested the hypothesis that capillary density is related to claudication times and anaerobic threshold (AT) in patients with PAD. A total of 37 patients with PAD and 29 control subjects performed cardiopulmonary exercise testing on a treadmill for AT and gastrocnemius muscle biopsies. Skeletal muscle capillary density was measured using immunofluorescence staining. PAD had decreased capillary density (278 ± 87 vs 331 ± 86 endothelial cells/mm2, p = 0.05), peak VO2 (15.7 ± 3.9 vs 24.3 ± 5.2 mL/kg/min, p ⩽ 0.001), and VO2 at AT (11.5 ± 2.6 vs 16.1 ± 2.8 mL/kg/min, p ⩽ 0.001) compared to control subjects. In patients with PAD, but not control subjects, capillary density was related to VO2 at AT ( r = 0.343; p = 0.038), time to AT ( r = 0.381; p = 0.020), and time after AT to test termination ( r = 0.610; p ⩽ 0.001). Capillary density was also related to time to claudication ( r = 0.332; p = 0.038) and time after claudication to test termination ( r = 0.584; p ⩽ 0.001). In conclusion, relationships between capillary density, AT, and claudication symptoms indicate that, in PAD, exercise limitations are likely partially dependent on limited skeletal muscle capillary density and oxidative metabolism.

Mitochondrial DNA damage in calf skeletal muscle and walking performance in people with peripheral artery disease

2020 ◽  
Vol 160 ◽  
pp. 680-689 ◽  
Author(s):  
Sunil K. Saini ◽  
Mary M. McDermott ◽  
Anna Picca ◽  
Lingyu Li ◽  
Stephanie E. Wohlgemuth ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Damage ◽  
Mitochondrial Dna ◽  
Peripheral Artery Disease ◽  
Peripheral Artery ◽  
Mitochondrial Dna Damage ◽  
Walking Performance ◽  
Artery Disease

Effects of Clustered Comorbid Conditions on Walking Capacity in Patients with Peripheral Artery Disease

2014 ◽  
Vol 28 (2) ◽  
pp. 279-283 ◽  
Author(s):  
Breno Quintella Farah ◽  
Raphael Mendes Ritti-Dias ◽  
Gabriel Grizzo Cucato ◽  
Marcel da Rocha Chehuen ◽  
João Paulo dos Anjos Souza Barbosa ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Comorbid Conditions ◽  
Peripheral Artery ◽  
Walking Capacity ◽  
Artery Disease
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