RESUMO
Patients with peripheral artery disease (PAD) have reduced muscle capillary density. Walking training (WT) is recommended for PAD patients. The goal of the study was to verify whether WT promotes angiogenesis in PAD-affected muscle and to investigate the possible role of miRNA-126 and the vascular endothelium growth factor (VEGF) angiogenic pathways on this adaptation. Thirty-two men with PAD were randomly allocated to two groups: WT (n = 16, 2 sessions/week) and control (CO, n = 16). Maximal treadmill tests and gastrocnemius biopsies were performed at baseline and after 12 weeks. Histological and molecular analyses were performed by blinded researchers. Maximal walking capacity increased by 65% with WT. WT increased the gastrocnemius capillary-fiber ratio (WT = 109 ± 13 vs. 164 ± 21 and CO = 100 ± 8 vs. 106 ± 6%, p < 0.001). Muscular expression of miRNA-126 and VEGF increased with WT (WT = 101 ± 13 vs. 130 ± 5 and CO = 100 ± 14 vs. 77 ± 20%, p < 0.001; WT = 103 ± 28 vs. 153 ± 59 and CO = 100 ± 36 vs. 84 ± 41%, p = 0.001, respectively), while expression of PI3KR2 decreased (WT = 97 ± 23 vs. 75 ± 21 and CO = 100 ± 29 vs. 105 ± 39%, p = 0.021). WT promoted angiogenesis in the muscle affected by PAD, and miRNA-126 may have a role in this adaptation by inhibiting PI3KR2, enabling the progression of the VEGF signaling pathway.
Assuntos
MicroRNAs , Doença Arterial Periférica , Masculino , Humanos , Claudicação Intermitente/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Doença Arterial Periférica/genética , Doença Arterial Periférica/metabolismo , Músculo Esquelético/metabolismo , Caminhada/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
OBJECTIVE: Peripheral arterial disease (PAD) is characterized by intermittent claudication, which interferes with walking and leads to worsening of functional capacity. This mechanism has not been clearly defined in PAD. Thus, the aim of our study was to identify the muscular metabolism and vascular function variables using near-infrared spectroscopy (NIRS) and their possible associations with functional capacity in individuals with PAD and secondly to verify the differences in these variables between persons with PAD and diabetes mellitus (DM) and those with PAD without DM. METHODS: A total of 39 participants with intermittent claudication were enrolled, 14 of whom had DM. They were assessed for functional capacity by the total distance covered in the treadmill test with the speed and grade constant and for muscle function and metabolism using near-infrared spectroscopy at rest and during the treadmill test. The Spearman correlation coefficient was computed to assess the presence of an association between the variables, and multiple linear regression analysis was performed, considering the total test distance as the dependent variable. The assessment between groups was performed using the independent t test or Mann-Whitney U test. RESULTS: The near-infrared spectroscopy variables related to tissue oxygen saturation in the test recovery phase were correlated with the functional performance during the treadmill test. Thus, those with a longer or slower recovery time and those with greater tissue deoxygenation had walked a shorter distance. A significant difference (P = .049) was noted between those with PAD stratified by DM in the reoxygenation time required for an occlusion. CONCLUSIONS: These findings reinforce the hypothesis that peripheral factors related to vascular function and muscular metabolism can affect the walking capacity of persons with PAD and that microvascular dysfunction is more prevalent among those with PAD and DM.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/fisiologia , Tolerância ao Exercício/fisiologia , Claudicação Intermitente/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxigênio/fisiologia , Caminhada/fisiologia , Diabetes Mellitus Tipo 2/complicações , Feminino , Seguimentos , Humanos , Claudicação Intermitente/complicações , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Estudos Retrospectivos , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
OBJECTIVE: We have previously shown that exogenous administration of the nuclear protein high mobility group box 1 (HMGB1) improves angiogenesis after tissue ischemia. Antagonizing HMGB1 prolongs muscle necrosis and deters regeneration. In this study, we evaluated HMGB1 expression in peripheral arterial disease (PAD) and the mechanisms that promote its release in a murine model of hindlimb ischemia. Specifically, we investigated how chloroquine (CQ), a commonly employed disease-modifying antirheumatic drug, promotes HMGB1 release from muscle. We hypothesized that CQ could increase HMGB1 locally and systemically, allowing it to mediate recovery from ischemic injury. METHODS: Muscle biopsies were performed on patients undergoing lower extremity surgery for non-PAD-related disease as well as for claudication and critical limb ischemia. Clinical symptoms and ankle-brachial indices were recorded for each patient. HMGB1 was detected in muscle sections using immunohistochemical staining. Unilateral femoral artery ligation was performed on both wild-type and inducible HMGB1 knockout mice. Wild-type mice were administered intraperitoneal CQ 2 weeks before and after femoral artery ligation. Laser Doppler perfusion imaging was used to determine perfusion recovery. Serum and tissue levels of HMGB1 were measured at designated time points. In vitro, cultured C2C12 myoblasts were treated with increasing doses of CQ. HMGB1, autophagosome formation, p62/SQSTM1 accumulation, caspase-1 expression and activity, and lactate dehydrogenase levels were measured in supernatants and cell lysates. RESULTS: Nuclear expression of HMGB1 was prominent in patients with claudication and critical limb ischemia (P < .05) compared with controls. CQ-treated mice had elevated serum HMGB1 and diffuse HMGB1 staining in muscle (P < .01). In wild-type mice, CQ treatment resulted in higher laser Doppler perfusion imaging ratios in the ischemic limb at 7 days (P < .03) and less fat replacement after 2 weeks (P < .03). In cultured myoblasts, CQ induced autophagosome accumulation, inhibited p62/SQSTM-1 degradation, and activated caspase-1. CONCLUSIONS: HMGB1 is prominently expressed in PAD muscle but mostly confined to the nucleus. Our in vivo data suggest that HMGB1 mobilization into the sarcoplasm and serum can be increased with CQ, possibly through caspase-1-mediated pathways. Whereas HMGB1 can be released by many cell types, these studies suggest that the muscle may be an important additional source that is relevant in PAD.
Assuntos
Cloroquina/farmacologia , Artéria Femoral/cirurgia , Proteína HMGB1/metabolismo , Claudicação Intermitente/tratamento farmacológico , Isquemia/tratamento farmacológico , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Doença Arterial Periférica/tratamento farmacológico , Idoso , Animais , Autofagia/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo , Estudos de Casos e Controles , Caspase 1/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Feminino , Proteína HMGB1/deficiência , Proteína HMGB1/genética , Humanos , Claudicação Intermitente/metabolismo , Claudicação Intermitente/patologia , Isquemia/metabolismo , Isquemia/patologia , L-Lactato Desidrogenase/metabolismo , Ligadura , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/patologia , Recuperação de Função Fisiológica , Fluxo Sanguíneo Regional , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
No study has shown the effects of acute resistance exercise on vasodilatory capacity of patients with peripheral artery disease. The aim of this study was to analyse the effects of a single session of resistance exercise on blood flow, reactive hyperemia, plasma nitrite, and plasma malondialdehyde in patients with peripheral artery disease. Fourteen peripheral artery disease patients underwent, in a random order, 2 experimental sessions: control (rest for 30 min) and resistance exercise (8 exercises, 2 sets of 10 repetitions at an intensity of 5-7 in the OMNI Resistance Exercise Scale). Blood flow, reactive hyperemia, plasma nitrite, and malondialdehyde were measured before and 40 min after the interventions in both sessions. Data were compared between sessions by analysis of covariance, using pre-intervention values as covariates. The increases in blood flow, reactive hyperemia, and log plasma nitrite were greater (p ≤ 0.05) after resistance exercise than the control session (3.2 ± 0.1 vs. 2.7 ± 0.1 mL · 100 mL(-1) tissue · min(-1), 8.0 ± 0.1 vs. 5.7 ± 0.1 AU, and 1.36 ± 0.01 vs. 1.26 ± 0.01 µmol â L(-1), respectively). On the other hand, malondialdehyde was similar between sessions (p > 0.05). In peripheral arterial disease patients, a single session of resistance exercise increases blood flow and reactive hyperemia, which seems to be mediated, in part, by increases in nitric oxide release.
Assuntos
Claudicação Intermitente/terapia , Perna (Membro)/irrigação sanguínea , Fluxo Sanguíneo Regional , Treinamento Resistido , Vasodilatação , Idoso , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hiperemia/etiologia , Hipertensão/etiologia , Claudicação Intermitente/etiologia , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Peroxidação de Lipídeos , Masculino , Malondialdeído/sangue , Microvasos/metabolismo , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Nitritos/sangue , Nitritos/metabolismo , Doença Arterial Periférica/fisiopatologia , Treinamento Resistido/efeitos adversosRESUMO
OBJECTIVE: To assess the acute metabolic and cardiovascular responses to walking exercise at an intensity corresponding to the heart rate of claudication pain onset and to investigate the effects of a 12-week walking training program at this intensity on walking capacity. METHODS: Twenty-nine patients with intermittent claudication were randomly allocated to the walking training (n=17) or control (CO, n=12) group. The walking training group performed an acute exercise session comprising 15×2-min bouts of walking at the heart rate of claudication pain onset, with 2-min interpolated rest intervals. The claudication symptoms and cardiovascular and metabolic responses were evaluated. Walking training was then performed at the same intensity twice each week for 12 weeks, while the control group engaged in twice weekly stretching classes. The claudication onset distance and total walking distance were evaluated before and after the interventions. Brazilian Registry Clinical Trials: RBR-7M3D8W. RESULTS: During the acute exercise session, the heart rate was maintained within tight limits. The exercise intensity was above the anaerobic threshold and >80% of the heart rate peak and VO2peak. After the exercise training period, the walking exercise group (n=13) showed increased claudication onset distance (309±153 vs. 413±201m) and total walking distance (784±182 vs. 1,100±236m) compared to the control group (n=12) (p<0.05). CONCLUSION: Walking exercise prescribed at the heart rate of claudication pain onset enables patients with intermittent claudication to exercise with tolerable levels of pain and improves walking performance.
Assuntos
Terapia por Exercício/métodos , Frequência Cardíaca/fisiologia , Claudicação Intermitente/terapia , Caminhada/fisiologia , Idoso , Análise de Variância , Teste de Esforço , Feminino , Humanos , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Medição da Dor , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the acute metabolic and cardiovascular responses to walking exercise at an intensity corresponding to the heart rate of claudication pain onset and to investigate the effects of a 12-week walking training program at this intensity on walking capacity. METHODS: Twenty-nine patients with intermittent claudication were randomly allocated to the walking training (n = 17) or control (CO, n = 12) group. The walking training group performed an acute exercise session comprising 15×2-min bouts of walking at the heart rate of claudication pain onset, with 2-min interpolated rest intervals. The claudication symptoms and cardiovascular and metabolic responses were evaluated. Walking training was then performed at the same intensity twice each week for 12 weeks, while the control group engaged in twice weekly stretching classes. The claudication onset distance and total walking distance were evaluated before and after the interventions. Brazilian Registry Clinical Trials: RBR-7M3D8W. RESULTS: During the acute exercise session, the heart rate was maintained within tight limits. The exercise intensity was above the anaerobic threshold and >80% of the heart rate peak and VO2peak. After the exercise training period, the walking exercise group (n = 13) showed increased claudication onset distance (309±153 vs. 413±201m) and total walking distance (784±182 vs. 1,100±236m) compared to the control group (n = 12) (p<0.05). CONCLUSION: Walking exercise prescribed at the heart rate of claudication pain onset enables patients with intermittent claudication to exercise with tolerable levels of pain and improves walking performance. .
Assuntos
Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia por Exercício/métodos , Frequência Cardíaca/fisiologia , Claudicação Intermitente/terapia , Caminhada/fisiologia , Análise de Variância , Teste de Esforço , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Consumo de Oxigênio/fisiologia , Medição da Dor , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: This study assessed the relationship between lower limb hemodynamics and metabolic parameters with walking tolerance in patients with intermittent claudication (IC). PATIENTS AND METHODS: Resting ankle-brachial index (ABI), baseline blood flow (BF), BF response to reactive hyperemia (BFRH), oxygen uptake (VO2), initial claudication distance (ICD) and total walking distance (TWD) were measured in 28 IC patients. Pearson and Spearman correlations were calculated. RESULTS: ABI, baseline BF and BF response to RH did not correlate with ICD or TWD. VO2 at first ventilatory threshold and VO2peak were significantly and positively correlated with ICD (r = 0.41 and 0.54, respectively) and TWD (r = 0.65 and 0.71, respectively). CONCLUSIONS: VO2peak and VO2 at first ventilatory threshold, but not ABI, baseline BF and BFHR were associated with walking tolerance in IC patients. These results suggest that VO2 at first ventilatory threshold may be useful to evaluate walking tolerance and improvements in IC patients.
Assuntos
Teste de Esforço , Tolerância ao Exercício , Claudicação Intermitente/diagnóstico , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Ventilação Pulmonar , Caminhada , Idoso , Limiar Anaeróbio , Índice Tornozelo-Braço , Brasil , Hemodinâmica , Humanos , Hiperemia/fisiopatologia , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Extremidade Inferior , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Valor Preditivo dos Testes , Fluxo Sanguíneo RegionalRESUMO
Although vascular remodeling is important in preventing tissue damage and restoring muscle function, there is no evidence of a relationship between vascular remodeling and muscle function after peripheral vascular occlusion. Nitric oxide (NO) has been implicated in the process of vascular remodeling in hindlimb ischemia. Thus, development of alterations in hindlimb gait after ischemia may be associated with impaired nitric oxide-dependent, vascular blood flow recovery. We evaluated hindlimb gait as an index of ischemia-induced revascularization and tested the effects of NO synthase inhibition on both hindlimb blood flow and hindlimb gait locomotion. After 14 days of ischemia, the ischemic hindlimb showed no significant differences in gait locomotion compared to the sham-operated hindlimb. However, hindlimb ischemia drastically reduced hindlimb blood flow from 46+/-3 mL/min/100 g to 12+/-2 mL/min/100 g which reverted to 33+/-5 mL/min/100 g after 14 days of ischemia. eNOS mRNA expression levels at 3, 7, 14, and 28 days after initiation of ischemia, were increased by 50+/-5%, 100+/-10%, 140+/-8% and 270+/-12% respectively and eNOS protein expression levels at 7, 14, and 28 days, were increased by 28+/-3%, 62+/-6% and 80+/-16% respectively. However, eNOS inhibition caused by l-NAME treatment prevented blood flow recovery and correction of abnormal gait locomotion in rats. Thus, the duration of the stride-swing phase increased and the stride length decreased. The knee joint angle decreased during flexion and extension with eNOS inhibition. In conclusion, ischemia-induced revascularization is associated with recovery of both hindlimb blood flow and normal gait locomotion. Moreover, prevention of NO synthesis, a key messenger in ischemia-induced revascularization, is associated with impairment in hindlimb locomotion. Thus, gait locomotion represents a functional model that could be used to evaluate the degree of ischemia-induced revascularization.