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Background: The circulating level of trimethylamine N-oxide (TMAO) has been reported to be associated with the prognosis of of peripheral arterial disease (PAD) patients. However, the effects of TMAO on neovascularization and perfusion recovery after PAD are not known., Methods: Unilateral hindlimb ischemia was generated in mice as experimental PAD model, TMAO or 3,3-dimethyl-1-butanol (DMB) were added to the drinking water for these mice. In cultured endothelial cells, TMAO was added to culture medium to assess the effects on cell viability and tube formation under simulated ischemic conditions., Results: In experimental PAD, TMAO treatment increased malondialdehyde (MDA), interleukin (IL)-1β and IL-6 in the ischemic muscle, impaired perfusion recovery, and decreased capillary density. On the other hand, mice fed with DMB drinking water showed lower TMAO level, interleukin (IL)-1β and IL-6, and higher vascular endothelial growth factor in the ischemic muscle, and better perfusion recovery after experimental PAD. In cultured endothelial cell, TMAO decreased intracellular nitric oxide, cell viability and tube formation, and increased intracellular reactive oxygen species levels., Conclusions: TMAO increases oxidative stress and inflammation, and impairs perfusion recovery and angiogenesis in experimental PAD., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Diabetes is a strong risk factor of peripheral arterial disease (PAD), and also leads to impaired perfusion recovery in the ischemic limb, which eventually results in poor outcomes in PAD patients. Sodium Tanshinone IIA Sulfonate (STS), a monomer from herbs, has been shown to improve the outcomes in a variety of ischemic disease including myocardial infarction. However, the effects of STS treatment in PAD is not known., Methods and Results: Unilateral femoral artery was ligated in mice as experimental PAD models, STS treatment improved perfusion recovery, increased capillary densities, decreased reactive oxygen species (ROS) level and microRNA-133a (miR-133a) expression in the ischemic hindlimb in diabetic mice; however, STS did not change perfusion recovery in non-diabetic C57BL/6 mice. Ischemic muscle tissue from diabetic mice was harvested 7 days after femoral ligation for biochemical test, STS resulted in reduced malondialdehyde (MDA), and increased GTP cyclohydrolase 1 (GCH1) and cyclic guanine monophosphate (cGMP) levels. In addition, STS treatment increased miR-133a expression in endothelial cells isolated from ischemic muscle tissue of diabetic mice. In endothelial cells cultured in high glucose medium, STS increased tube formation and nitric oxide (NO) production, and reduced cellular ROS level and miR-133a expression under simulated ischemic condition. In addition, GCH1 inhibitor or miR-133a overexpression using exogenous microRNA mimic blunted STS-induced angiogenic effects and ROS neutralization in cultured endothelial cells under hyperglycemic and hypoxic conditions., Conclusion: These findings demonstrate STS improves angiogenesis via inhibiting miR-133a expression and increasing GCH-1 protein levels in experimental PAD with diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Peripheral arterial disease (PAD) patients with diabetes mellitus suffer from impaired neovascularization after ischemia which results in poorer outcomes. MicroRNA (miR)-133a is excessively expressed in endothelial cells under diabetic conditions. Here, we test whether diabetes-induced miR-133a up-regulation is involved in the impaired capability of neovascularization in experimental PAD models. Methods and results: MiR-133a level was measured by quantitative RT-PCR and showed a higher expression level in the ischemic muscle from diabetic mice when compared with nondiabetic mice. Knockdown of miR-133a using antagomir improved perfusion recovery and angiogenesis in experimental PAD model with diabetes day 21 after HLI. On the other hand, overexpression of miR-133a impaired perfusion recovery. Ischemic muscle was harvested day 7 after experimental PAD for biochemical test, miR-133a antagonism resulted in reduced malondialdehyde, and it increased GTP cyclohydrolase 1 (GCH1), and cyclic guanine monophosphate (cGMP) levels. In cultured endothelial cells, miR-133a antagonism resulted in reduced reactive oxygen species level, and it increased tube formation, nitric oxide (NO), and cGMP level. Moreover, miR-133a antagonism-induced angiogenesis was abolished by GCH1 inhibitor. In contrary, miR-133a overexpression impairs angiogenesis and it reduces GCH1, NO, and cGMP levels in nondiabetic models. Conclusion: Diabetes mellitus-induced miR-133a up-regulation impairs angiogenesis in PAD by reducing NO synthesis in endothelial cells. MiR-133a antagonism improves postischemic angiogenesis., (© 2018 The Author(s).)

In peripheral arterial disease (PAD) patients, occlusions in the major arteries that supply the leg makes blood flow dependent on the capacity of neovascularization. There is no current medication that is able to increase neovascularization to the ischemic limb and directly treat the primary problem of PAD. An increasing body of evidence supports the notion that inflammation plays an important role in the vascular remodeling and perfusion recovery after PAD. Interleukins (ILs), a group of proteins produced during inflammation, have been considered to be important for angiogenesis and arteriogenesis after tissue ischemia. This review summarizes the latest clinical and experimental developments of the role of ILs in blood perfusion recovery after PAD., (© 2018 The Author(s).)