Smoking and the Pathophysiology of Peripheral Artery Disease

Smoking is one of the most important preventable factors causing peripheral artery disease (PAD). The purpose of this review is to comprehensively analyze and summarize the pathogenesis and clinical characteristics of smoking in PAD based on existing clinical, in vivo, and in vitro studies. Extensive searches and literature reviews have shown that a large amount of data exists on the pathological process underlying the effects of cigarette smoke and its components on PAD through various mechanisms. Cigarette smoke extracts (CSE) induce endothelial cell dysfunction, smooth muscle cell remodeling and macrophage phenotypic transformation through multiple molecular mechanisms. These pathological changes are the molecular basis for the occurrence and development of peripheral vascular diseases. With few discussions on the topic, we will summarize recent insights into the effect of smoking on regulating PAD through multiple pathways and its possible pathogenic mechanism.

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Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease

Vascular Medicine ◽

10.1177/1358863x19866254 ◽

2019 ◽

Vol 24 (5) ◽

pp. 395-404 ◽

Cited By ~ 2

Author(s):

Satyanarayana Alleboina ◽

Dawit Ayalew ◽

Rahul Peravali ◽

Lingdan Chen ◽

Thomas Wong ◽

...

Keyword(s):

Endothelial Cells ◽

Peripheral Artery Disease ◽

Molecular Mechanisms ◽

Endothelial Cell Proliferation ◽

Peripheral Artery ◽

Vessel Occlusion ◽

Dual Specificity Phosphatase ◽

Dual Specificity ◽

Artery Disease

Peripheral artery disease (PAD) is caused by atherosclerotic occlusions of vessels outside the heart, particularly those of the lower extremities. Angiogenesis is one critical physiological response to vessel occlusion in PAD, but our understanding of the molecular mechanisms involved in angiogenesis is incomplete. Dual specificity phosphatase 5 (DUSP5) has been shown to play a key role in embryonic vascular development, but its role in post-ischemic angiogenesis is not known. We induced hind limb ischemia in mice and found robust upregulation of Dusp5 expression in ischemic hind limbs. Moreover, in vivo knockdown of Dusp5 resulted in impaired perfusion recovery in ischemic limbs and was associated with increased limb necrosis. In vitro studies showed upregulation of DUSP5 in human endothelial cells exposed to ischemia, and knockdown of DUSP5 in these ischemic endothelial cells resulted in impaired endothelial cell proliferation and angiogenesis, but did not alter apoptosis. Finally, we show that these effects of DUSP5 on post-ischemic angiogenesis are a result of DUSP5-dependent decrease in ERK1/2 phosphorylation and p21 protein expression. Thus, we have identified a role of DUSP5 in post-ischemic angiogenesis and implicated a DUSP5-ERK-p21 pathway that may serve as a therapeutic target for the modulation of post-ischemic angiogenesis in PAD.

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Polyunsaturated fatty acids and peripheral artery disease

Vascular Medicine ◽

10.1177/1358863x11429175 ◽

2012 ◽

Vol 17 (1) ◽

pp. 51-63 ◽

Cited By ~ 17

Author(s):

S Marlene Grenon ◽

Millie Hughes-Fulford ◽

Joseph Rapp ◽

Michael S Conte

Keyword(s):

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Peripheral Artery Disease ◽

In Vivo Studies ◽

Peripheral Artery ◽

Beneficial Effects ◽

Epidemiological Surveys ◽

Artery Disease

There is substantial evidence that polyunsaturated fatty acids (PUFAs) such as n-3 and n-6 fatty acids (FAs) play an important role in prevention of atherosclerosis. In vitro and in vivo studies focusing on the interactions between monocytes and endothelial cells have explored the molecular effects of FAs on these interactions. Epidemiological surveys, followed by large, randomized, control trials have demonstrated a reduction in major cardiovascular events with supplementation of n-3 FAs in secondary prevention settings. The evidence of beneficial effects specific to patients with peripheral artery disease (PAD) remains elusive, and is the focus of this review.

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Corilagin Ameliorates Atherosclerosis in Peripheral Artery Disease via the Toll-Like Receptor-4 Signaling Pathway in vitro and in vivo

Frontiers in Immunology ◽

10.3389/fimmu.2020.01611 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yiqing Li ◽

Yujie Wang ◽

Yunfei Chen ◽

Yao Wang ◽

Shaojun Zhang ◽

...

Keyword(s):

Signaling Pathway ◽

Peripheral Artery Disease ◽

Toll Like Receptor ◽

Peripheral Artery ◽

Toll Like Receptor 4 ◽

Artery Disease

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Corilagin Ameliorates Atherosclerosis in Peripheral Artery Disease via TLR4 Signal Pathway in vitro and in vivo

SSRN Electronic Journal ◽

10.2139/ssrn.3424179 ◽

2019 ◽

Author(s):

Yi-Qing Li ◽

Yu-Jie Wang ◽

Yun-Fei Chen ◽

Yao Wang ◽

Shao-Jun Zhang ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Signal Pathway ◽

Peripheral Artery ◽

Artery Disease

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Oxygen availability and skeletal muscle oxidative capacity in patients with peripheral artery disease: implications from in vivo and in vitro assessments

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00641.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. H897-H909 ◽

Cited By ~ 11

Author(s):

Corey R. Hart ◽

Gwenael Layec ◽

Joel D. Trinity ◽

Yann Le Fur ◽

Jayson R. Gifford ◽

...

Keyword(s):

Skeletal Muscle ◽

Peripheral Artery Disease ◽

Early Stage ◽

Oxidative Capacity ◽

Muscle Dysfunction ◽

Peripheral Artery ◽

Skeletal Muscle Dysfunction ◽

Artery Disease

Evidence suggests that the peak skeletal muscle mitochondrial ATP synthesis rate ( Vmax) in patients with peripheral artery disease (PAD) may be attenuated due to disease-related impairments in O2 supply. However, in vitro assessments suggest intrinsic deficits in mitochondrial respiration despite ample O2 availability. To address this conundrum, Doppler ultrasound, near-infrared spectroscopy, phosphorus magnetic resonance spectroscopy, and high-resolution respirometry were combined to assess convective O2 delivery, tissue oxygenation, Vmax, and skeletal muscle mitochondrial capacity (complex I + II, state 3 respiration), respectively, in the gastrocnemius muscle of 10 patients with early stage PAD and 11 physical activity-matched healthy control (HC) subjects. All participants were studied in free-flow control conditions (FF) and with reactive hyperemia (RH) induced by a period of brief ischemia during the last 30 s of submaximal plantar flexion exercise. Patients with PAD repeated the FF and RH trials under hyperoxic conditions (FF + 100% O2 and RH + 100% O2). Compared with HC subjects, patients with PAD exhibited attenuated O2 delivery at the same absolute work rate and attenuated tissue reoxygenation and Vmax after relative intensity-matched exercise. Compared with the FF condition, only RH + 100% O2 significantly increased convective O2 delivery (~44%), tissue reoxygenation (~54%), and Vmax (~60%) in patients with PAD ( P < 0.05), such that Vmax was now not different from HC subjects. Furthermore, there was no evidence of an intrinsic mitochondrial deficit in PAD, as assessed in vitro with adequate O2. Thus, in combination, this comprehensive in vivo and in vitro investigation implicates O2 supply as the predominant factor limiting mitochondrial oxidative capacity in early stage PAD. NEW & NOTEWORTHY Currently, there is little accord as to the role of O2 availability and mitochondrial function in the skeletal muscle dysfunction associated with peripheral artery disease. This is the first study to comprehensively use both in vivo and in vitro approaches to document that the skeletal muscle dysfunction associated with early stage peripheral artery disease is predominantly a consequence of limited O2 supply and not the impact of an intrinsic mitochondrial defect in this pathology.

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Soluble CD40L in peripheral artery disease

Thrombosis and Haemostasis ◽

10.1160/th04-09-0586 ◽

2005 ◽

Vol 93 (03) ◽

pp. 578-583 ◽

Cited By ~ 31

Author(s):

Kiat Tan ◽

Muzahir Tayebjee ◽

Indran Davagnanam ◽

Mark Moss ◽

Gregory Lip ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Sole Source ◽

Clinical Severity ◽

Healthy Controls ◽

Peripheral Artery ◽

Platelet Surface ◽

Soluble Cd40l ◽

Soluble P ◽

Artery Disease

SummaryAlthough soluble CD40L (sCD40L, possibly derived from platelets and pro-inflammatory in vitro) may be implicated in thrombosis and haemostasis, there are little data in peripheral artery disease (PAD). We hypothesised the following: (a) that sCD40L relates to the clinical severity of PAD; and (b) that peripheral artery angioplasty acutely raises sCD40L levels. sCD40L was compared to established platelet markers soluble P selectin, platelet microparticles and platelet surface expression of CD62 and CD63. We recruited 36 healthy controls, 33 patients with intermittent claudication (IC), and 33 with symptomatically more severe critical limb is chaemia (CLI), measuring plasma markers by ELISA and membrane markers by flow cytometry. Eleven patients with CLI subsequently underwent peripheral artery angioplasty: blood was taken before and 10 minutes after the intervention. Results show that sCD40L was raised in IC at median 68 (IQR 28–333) pg/ml and in CLI at 64 (34–282) pg/mL compared to 35 (IQR 28–55) pg/ml in the healthy controls (p=0.009). Levels were no different between IC and CLI. The same distribution pattern was present for soluble P selectin, %platelets CD62+ve and CD63+ve. sCD40L failed to correlate significantly with ABPI (p=0.264), unlike %platelets CD62+ve (p=0.0032) and CD63+ve (p=0.009). Pre-angioplasty sCD40L level of 72 (35–610) ng/ml rose to 100 ng/ml (IQR=60–237)(p=0.018) post–angioplasty. Plasma sCD40L, in addition to other platelet indices, is raised in peripheral atherosclerosis and is increased by peripheral artery angioplasty, although levels seem unrelated to clinical severity. Failure to correlate with other markers suggest the platelet may not be the sole source of sCD40L, and that other cells may contribute to plasma levels.

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Prevalence, Correlates, and Prognosis of Peripheral Artery Disease in Rural Ecuador—Rationale, Protocol, andPhase IResults of a Population-Based Survey: An Atahualpa Project-Ancillary Study

International Journal of Vascular Medicine ◽

10.1155/2014/643589 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Oscar H. Del Brutto ◽

Mark J. Sedler ◽

Robertino M. Mera ◽

Pablo R. Castillo ◽

Elizabeth H. Cusick ◽

...

Keyword(s):

Phase I ◽

Peripheral Artery Disease ◽

Cardiovascular Health ◽

Ankle Brachial Index ◽

Vascular Diseases ◽

Population Based ◽

Test Reliability ◽

Phase Iii ◽

Peripheral Artery ◽

Artery Disease

Background. Little is known on the prevalence of peripheral artery disease (PAD) in developing countries.Study design. Population-based study in Atahualpa. InPhase I, the Edinburgh claudication questionnaire (ECQ) was used for detection of suspected symptomatic PAD; persons with a negative ECQ but a pulse pressure ≥65 mmHg were suspected of asymptomatic PAD. InPhase II, the ankle-brachial index will be used to test reliability of screening instruments and to determine PAD prevalence. InPhase III, participants will be followed up to estimate the relevance of PAD as a predictor of vascular outcomes.Results. DuringPhase I, 665 Atahualpa residents aged ≥40 years were enrolled (mean age: 59.5 ± 12.6 years, 58% women). A poor cardiovascular health status was noticed in 464 (70%) persons of which 27 (4%) had a stroke and 14 (2%) had ischemic heart disease. Forty-four subjects (7%) had suspected symptomatic PAD and 170 (26%) had suspected asymptomatic PAD. Individuals with suspected PAD were older, more often women, and had a worse cardiovascular profile than those with nonsuspected PAD.Conclusions. Prevalence of suspected PAD in this underserved population is high. Subsequent phases of this study will determine whether prompt detection of PAD is useful to reduce the incidence of catastrophic vascular diseases in the region.

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Role of genetics in peripheral arterial disease outcomes; significance of limb-salvage quantitative locus-1 genes

Experimental Biology and Medicine ◽

10.1177/1535370217743460 ◽

2017 ◽

Vol 243 (2) ◽

pp. 190-197 ◽

Cited By ~ 1

Author(s):

Emmanuel Okeke ◽

Ayotunde O Dokun

Keyword(s):

Quantitative Trait Locus ◽

Limb Salvage ◽

Disease Severity ◽

Peripheral Artery Disease ◽

Quantitative Trait ◽

Molecular Mechanisms ◽

Limb Ischemia ◽

Peripheral Artery ◽

Trait Locus ◽

Artery Disease

Peripheral artery disease is a major health care problem with significant morbidity and mortality. Humans with peripheral artery disease exhibit two major and differential clinical manifestations – intermittent claudication and critical limb ischemia. Individuals with intermittent claudication or critical limb ischemia have overlapping risk factors and objective measures of blood flow. Hence, we hypothesized that variation in genetic make-up may be an important determinant in the severity of peripheral artery disease. Previous studies have identified polymorphism in genes, contributing to extent of atherosclerosis but much less is known about polymorphisms associated with genes that can influence peripheral artery disease severity. This review outlines some of the progress made up-to-date to unravel the molecular mechanisms underlining differential peripheral artery disease severity. By exploring the recovery phenotype of different mouse strains following experimental peripheral artery disease, our group identified the limb salvage-associated quantitative trait locus 1 on mouse chromosome 7 as the first genetic modifier of perfusion recovery and tissue necrosis phenotypes. Furthermore, a number of genes within LSq-1, such as ADAM12, IL-21Rα, and BAG3 were identified as genetic modifiers of peripheral artery disease severity that function through preservation of endothelial and skeletal muscle cells during ischemia. Taken together, these studies suggest manipulation of limb salvage-associated quantitative trait locus 1 genes show great promise as therapeutic targets in the management of peripheral artery disease. Impact statement Peripheral artery disease (PAD) is a major health care problem with significant morbidity and mortality. Individuals with similar atherosclerosis burden do display different severity of disease. This review outlines some of the progress made up-to-date in unraveling the molecular mechanisms underlining differential PAD severity with a focus on the role of the Limb Salvage-associated Quantitative trait locus 1 (LSq-1), a key locus in adaptation to ischemia in PAD.

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MiRNAs in peripheral artery disease - something gripping this way comes

VASA ◽

10.1024/0301-1526/a000345 ◽

2014 ◽

Vol 43 (3) ◽

pp. 163-170 ◽

Cited By ~ 5

Author(s):

Wanda Kloos ◽

Britta Vogel ◽

Erwin Blessing

Keyword(s):

Peripheral Artery Disease ◽

Molecular Mechanisms ◽

Cardiac Development ◽

Mirna Regulation ◽

Peripheral Artery ◽

Vascular Integrity ◽

Innovative Strategies ◽

Gene Sets ◽

Highly Sensitive ◽

Artery Disease

Peripheral artery disease (PAD) is a marker disease for generalized atherosclerosis and represents one of the worlds major causes of morbidity and mortality. Many studies have tried to gain insight into the molecular mechanisms involved in PAD onset, progression and prognosis. In the last decade, small non-coding RNAs, termed miRNAs, have emerged as a major research focus due to their regulating function of multiple gene sets. In the cardiovascular system, miRNAs not only impact on physiological pathways like cardiac development and angiogenesis, but also play an important role in disease mechanisms and progression of myocardial hypertrophy, acute myocardial infarction, heart failure or arrhythmias. New insights lend considerable support to the concept of miRNAs serving as highly sensitive biomarkers and therapeutic targets. To date, a comprehensive understanding of miRNA regulation of angiogenesis and maintenance of vascular integrity in PAD remains less explored. In this review, we discuss current studies and highlight the potential of miRNAs not only to act as a diagnostic tool, but also to facilitate innovative strategies for gene therapy.

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