Coronary arteries treated with plain balloon, DEB, BMS, and DES showed time-dependent loss of endothelial-dependent and -independent vasomotor function, with imbalanced contraction/dilation capacity.

Worsening renal function in decompensated cirrhosis is accompanied by progressive elevation in plasma NOx and L-Arg. These findings support the hypothesis that NO-mediated vasodilation is probably linked with the mechanism of progressive renal failure in decompensated cirrhotics.

Both Type 1 diabetes mellitus (DM1) and type 2 diabetes mellitus (DM2) are associated with an increased risk of limb amputation in peripheral arterial disease (PAD). How diabetes contributes to poor PAD outcomes is poorly understood but may occur through different mechanisms in DM1 and DM2. Previously, we identified a disintegrin and metalloproteinase gene 12 (ADAM12) as a key genetic modifier of post-ischemic perfusion recovery. In an experimental PAD, we showed that ADAM12 is regulated by miR-29a and this regulation is impaired in ischemic endothelial cells in DM1, contributing to poor perfusion recovery. Here we investigated whether miR-29a regulation of ADAM12 is altered in experimental PAD in the setting of DM2. We also explored whether modulation of miR-29a and ADAM12 expression can improve perfusion recovery and limb function in mice with DM2. Our result showed that in the ischemic limb of mice with DM2, miR-29a expression is poorly downregulated and ADAM12 upregulation is impaired. Inhibition of miR-29a and overexpression of ADAM12 improved perfusion recovery, reduced skeletal muscle injury, improved muscle function, and increased cleaved Tie 2 and AKT phosphorylation. Thus, inhibition of miR-29a and or augmentation of ADAM12 improves experimental PAD outcomes in DM2 likely through modulation of Tie 2 and AKT signalling.

Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, resulting in ischemic limb injuries. Individuals with diabetes and PAD typically have more severe ischemic limb injuries and limb amputations, but the mechanisms involved are poorly understood. Previously, we identified BAG3 as a gene within a mouse genetic locus termed limb salvage QTL1 on mouse chromosome 7 that determined the extent of limb necrosis following ischemic injury in C57Bl/6 mice. Whether BAG3 deficiency plays a role in the severe ischemic injury observed in diabetic PAD is not known. In vitro, we found simulated ischemia enhanced BAG3 expression in primary human skeletal muscle cells, whereas BAG3 knockdown increased necroptosis markers and decreased cell viability. In vivo, ischemic skeletal muscles from hind limbs of high-fat diet (HFD)-fed mice showed poor BAG3 expression compared to normal chow diet (NCD)-fed mice, and this was associated with increased limb amputations. BAG3 overexpression in ischemic skeletal muscles from hind limbs of HFD mice rescued limb amputation and improved autophagy, necroptosis, skeletal muscle function and regeneration. Therefore, BAG3 deficiency in ischemic skeletal muscles contributes to the severity of ischemic limb injury in diabetic PAD, likely through autophagy and necroptosis pathways.

BackgroundThe increased adverse cardiac events in women undergoing coronary artery bypass grafting are multifactorial and may include clinical, psychosocial, and biological factors. Potential contributing biological factors could include vascular hyperreactivity of the internal mammary artery (IMA) to endogenous vasoconstrictors in women, resulting in a predilection to myocardial ischemia. This study evaluated sex differences in serotonin and thromboxane A2 dependent vasoconstriction in human isolated IMA, with the mechanistic role of (1) the endothelium, (2) nitric oxide (NO), (3) prostaglandins, and (4) receptor activity investigated for any observed sex difference.Methods and ResultsViable isolated human IMA segments were obtained from 116 patients (44 women [mean age, 66.8±12.2 years] and 72 men [mean age, 66.6±10.4 years]) undergoing coronary artery bypass grafting. Cumulative concentration‐response curves for serotonin and thromboxane A2 mimetic, U46619, were determined and revealed an increased sensitivity to serotonin but not U46619 in women. This sex difference to serotonin was further assessed by the following: (1) endothelial denudation, (2) endothelial NO synthase inhibition and NO quantification using electron paramagnetic resonance, (3) cyclooxygenase inhibition and prostaglandin metabolite quantification using mass spectrometry, and (4) quantification of receptor activity status. The female hyperreactivity to serotonin was (1) abolished by endothelial denudation; (2) unaffected by NO synthase inhibition, with no difference in electron paramagnetic resonance–assessed NO levels; (3) abolished by cyclooxygenase inhibition (quantification of prostaglandins in IMA revealed a trend towards reduced 6‐keto prostaglandin F1α in female IMA; P=0.08); and (4) unrelated to receptor activity.ConclusionsThese data indicate that female IMAs are hyperreactive to serotonin but not U46619, with the former attributable to an endothelium‐dependent cyclooxygenase pathway.

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Heart valve tissue engineering and regeneration represents a novel, and viable alternative treatment modality for valvular heart disease. Tissue-engineered pulmonary valves (TEPV) have been constructed from autologous cells grown on 3D biodegradable scaffolds or decelluarized xeno-or homografts and surgically implanted in animal models. From a translational stand point, constructed valves must maintain regenerative competency in recipients, with minimum risk for stenosis over the long term. Stem cells are an attractive cell source for this proposed solution; candidate cells are expected to maintain robust differentiation and transdifferentiation capacity. Transplanted cells must persist, engraft, and couple electro-mechanically with endogenous tissue. Here, we present a discussion on the clinical applicability of bone marrow mesenchymal stem cells in TEPV.