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In experimental peripheral arterial disease, type 2 diabetes alters post-ischemic gene expression.

ABSTRACT: Peripheral arterial disease is characterized by impaired blood flow to tissues outside the heart due to atherosclerosis and it most frequently occurs in the lower extremities. Type 2 diabetes (T2D) is a well-known risk factor that accelerate the course and contributes to poor clinical outcomes of PAD. While there is some evidence that T2D is associated with altered expression of genes involved in regulating PAD severity, our knowledge about the specific genes and pathways involved remains incomplete. We induced experimental PAD or hind limb ischemia in T2D and non-diabetic mice and subjected the ischemic gastrocnemius muscle tissues to genome-wide mRNA transcriptome analysis. We subsequently performed pathway analysis on the top 500 genes that showed the most significant expression differences between the ischemic diabetic and ischemic non-diabetic muscle tissues. Pathway analysis of the differentially expressed genes identified pathways involved in essential biological processes such as "metabolic pathways," "phagosomes," "lysosomes," and "regulation of actin cytoskeleton". Overall, our data provides the opportunity to test hypotheses on the potential role of the altered genes/molecular pathways in poor PAD outcomes in diabetes.

SUBMITTER: Peravali R

PROVIDER: S-EPMC6595134 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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In experimental peripheral arterial disease, type 2 diabetes alters post-ischemic gene expression.

Peravali Rahul R Gunnels Lucas L Dhanabalan Karthik K Ariganjoye Folabi F Gerling Ivan C IC Dokun Ayotunde O AO

Journal of clinical & translational endocrinology 20190531

Peripheral arterial disease is characterized by impaired blood flow to tissues outside the heart due to atherosclerosis and it most frequently occurs in the lower extremities. Type 2 diabetes (T2D) is a well-known risk factor that accelerate the course and contributes to poor clinical outcomes of PAD. While there is some evidence that T2D is associated with altered expression of genes involved in regulating PAD severity, our knowledge about the specific genes and pathways involved remains incomp ...[more]

PMID: 31293900

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Project description:ObjectivePeripheral arterial disease (PAD) is a significant age-related medical condition with limited pharmacologic options. Severe PAD, termed critical limb ischemia, can lead to amputation. Skeletal muscle is the end organ most affected by PAD, leading to ischemic myopathy and debility of the patient. Currently, there are not any therapeutics to treat ischemic myopathy, and proposed biologic agents have not been optimized owing to a lack of preclinical models of PAD. Because a large animal model of ischemic myopathy may be useful in defining the optimal dosing and delivery regimens, the objective was to create and to characterize a swine model of ischemic myopathy that mimics patients with severe PAD.MethodsYorkshire swine (N = 8) underwent acute right hindlimb ischemia by endovascular occlusion of the external iliac artery. The effect of ischemia on limb function, perfusion, and degree of ischemic myopathy was quantified by weekly gait analysis, arteriography, hindlimb blood pressures, femoral artery duplex ultrasound scans, and histologic examination. Animals were terminated at 5 (n = 5) and 6 (n = 3) weeks postoperatively. Ossabaw swine (N = 8) fed a high-fat diet were used as a model of metabolic syndrome for comparison of arteriogenic recovery and validation of ischemic myopathy.ResultsThere was persistent ischemia in the right hindlimb, and occlusion pressures were significantly depressed compared with the untreated left hindlimb out to 6 weeks (systolic blood pressure, 31 ± 21 vs 83 ± 15 mm Hg, respectively; P = .0007). The blood pressure reduction resulted in a significant increase of ischemic myopathy in the gastrocnemius muscle in the treated limb. Gait analysis revealed a functional deficit of the right hindlimb immediately after occlusion that improved rapidly during the first 2 weeks. Peak systolic velocity values in the right common femoral artery were severely diminished throughout the entire study (P < .001), and the hemodynamic environment after occlusion was characterized by low and oscillatory wall shear stress. Finally, the internal iliac artery on the side of the ischemic limb underwent significant arteriogenic remodeling (1.8× baseline) in the Yorkshire but not in the Ossabaw swine model.ConclusionsThis model uses endovascular technology to produce the first durable large animal model of ischemic myopathy. Acutely (first 2 weeks), this model is associated with impaired gait but no tissue loss. Chronically (2-6 weeks), this model delivers persistent ischemia, resulting in ischemic myopathy similar to that seen in PAD patients. This model may be of use for testing novel therapeutics including biologic therapies for promoting neovascularization and arteriogenesis.

Dataset Information

In experimental peripheral arterial disease, type 2 diabetes alters post-ischemic gene expression.

Publications

In experimental peripheral arterial disease, type 2 diabetes alters post-ischemic gene expression.

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