Impaired hydrogen sulfide protein expression in patients with peripheral artery disease

INTRODUCTION: Hydrogen sulfide (H2S) is a gaseous signaling molecule that serves various roles in the vasculature, such as upregulating angiogenesis, vascular smooth muscle relaxation, protecting endothelial function, and regulating redox balance. Despite H2S’s positive impacts on vascular homeostasis, it is important to note that its actions depend on its concentrations. At high concentrations, H2S has been reported to increase oxidative stress damage, such as oxidation of cysteine residues and lipid peroxidation. This may indicate that H2S may act as a ‘double-edged sword’ in the field of vascular physiology. Peripheral artery disease (PAD) is an atherosclerotic disease which manifested by claudication (leg pain during walking). Growing evidence suggests that abnormal H2S level may present with vascular diseases, however, only a few animal studies investigated the H2S and H2S -mediated oxidative stress damage in vascular disease models, and there are currently no available studies for human vascular disease patients, such as patients with PAD. Therefore, the purpose of this study was to examine the H2S and oxidative stress damage in peripheral blood mononuclear cells (PBMCs) and skeletal muscle tissues from patients with PAD. METHODS: Western blot was performed using skeletal muscle tissues and PBMCs to examine protein expression of cystathionase (CTH), which catalyzes production of H2S, and glutathione peroxidase-4 (GPx-4) and catalase (CAT), which are antioxidant markers, from healthy adults (CON) and patients with PAD (PAD). RESULTS: Patients with PAD show a lower expression of CTH compared to CON (P \u3c 0.01, PAD: 1.61 ± 0.44, CON: 8.53 ± 0.46). However, CAT expression was not different between groups (P = 0.429, PAD: 0.03 ± 0.02, CON: 0.01 ± 0.01). In addition, CAT and GPx-4 expression was assessed in CON PBMCs (CAT: 5.07 ± 1.14, GPx-4: 0.63 ± 0.3). CONCLUSION: CTH protein expression in the skeletal muscle is attenuated in PAD compared to CON. However, CAT protein expression in the skeletal muscle is not different between groups. These data suggest an impairment is present in the H2S signaling system in the skeletal muscle of patients with PAD

Mitochondrial targeted antioxidant intake improves vascular function and exercise tolerance in peripheral artery disease patients

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes reduced blood flow and leg pain. This may be in part due to excessive mitochondria-produced reactive oxygen species (ROS) and attenuated mitochondrial respiratory function. Mitoquinol mesylate, a mitochondrial-targeted antioxidant, has been shown to scavenge ROS and improve vascular function in older adults and animal models. However, the impacts of mitoquinol on vascular function in PAD patients are unknown. We sought to examine the impacts of mitoquinol intake (80mg) on endothelial function (flow mediated dilation, FMD), resting heart rate (RHR), blood pressure (BP), arterial stiffness (pulse wave velocity, PWV), and exercise tolerance in PAD patients. 10 PAD patients (stage II-III) received either mitoquinol or placebo in a randomized crossover design. At each visit, measurements of RHR, BP, brachial and popliteal artery FMD, PWV, augmentation index (AIx), maximal walking capacity, and time to claudication (COT) were measured before and after mitoquinol and placebo. There were significant group by time interactions (ppp=0.10), carotid-to-ankle PWV (p=0.08), and increases in maximal walking time (p=0.06), and maximal walking distance (p=0.06). There were no changes in RHR, systolic BP, central BP, deceleration time, max dP/dt, carotid-to-radial PWV, carotid-to-femoral PWV, or AIx (p\u3e0.05). Mitoquinol intake may be an effective strategy for targeting mitochondrial ROS, which may be useful for treating endothelial dysfunction, leg pain, and improving walking time in PAD patients

Cardiovascular and Autonomic Responses to Acute Exposure to Mild Hypercapnic Conditions in Middle-Aged Adults

Sedentary lifestyle in the US has significantly increased in recent decades, specifically, adults in modern workplaces have been known to be exposed to ~6 hours of uninterrupted prolonged sitting (PS) per day. PS has been shown to cause endothelial dysfunction, leading to an increased risk for cardiovascular disease such as peripheral arterial disease. Additionally, elevations in carbon dioxide (hypercapnia), commonly observed in workplaces such as offices, have been known to impair cardiovascular function. Interrupting PS with muscular contractions has been used to prevent the negative effects of PS. However, the underlying protective mechanism(s) of these muscular contractions during PS with hypercapnia in middle-aged adults is currently unknown. The purpose of this study was to examine the impacts of muscle contraction, specifically, activation of group III/IV muscle afferents via passive and active leg movement in middle-aged office workers during PS in a mild-hypercapnic environment. Healthy sedentary middle-aged adults (n=5, age: 45 ± 9) completed 3 visits in a mild-hypercapnic environment: control (CON) passive (PASS) and active (ACT) to determine how activating group III/IV muscle afferents during 2.5 hours of PS affect cardiovascular function. Following PS, popliteal shear rate increased in ACT (23.98%) compared to PASS (4.09%) and CON (11.44%). Popliteal artery flow-mediated dilation showed greater increase in ACT (3.33%) compared to PASS (1.44%) and CON (1.12%). This study provides novel insight towards the cardiovascular effects of PS with mild hypercapnia in sedentary middle-aged adults, and the roles of group III and IV muscle afferent activation in the preservation for vascular function

Integrative function of microcirculation and skeletal muscle function in peripheral artery disease

Peripheral artery disease (PAD) is an atherosclerotic disease that impairs lower-extremity circulatory function. Attenuated skeletal muscle mitochondrial function and oxygen utility capacity have been reported in the ischemic limbs; however, the underlying mechanisms are not well-understood. We investigated the impacts of chronic ischemia on skeletal muscle arteriole vasodilatory function and its contribution to skeletal muscle mitochondrial function and microvascular oxygen delivery and utilization capacity (TOI) in PAD. Skeletal muscle and arteriole samples from patients with PAD (n=18, 68.4±10.2 years) and age-matched controls (CON, n=11, 64.6±9.3 years) were harvested. Endothelial-dependent and endothelial-independent vasodilatory function was assessed by flow, acetylcholine (ACh), and sodium nitroprusside (SNP), and skeletal muscle mitochondrial function was measured by high-resolution respirometry. TOI was assessed by near-infrared spectroscopy in-vivo. Endothelial-dependent vasodilation was attenuated in PAD in response to ACh (10-3M, CON: 71.1±7%, PAD: 45.5±6%, PP-3M, CON: 101.5±4%, PAD: 91.6±5%, P=0.12). Complex I + II state 3 respiration was lower in PAD (CON: 26.1±2.1, PAD: 7.8±1.4 pmol∙s-1∙mg-1, P-1, Pr=0.6 and r=0.5, respectively, Pr=0.5 and r=0.6, respectively,