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1.  Concise Review: Tissue-Engineered Vascular Grafts for Cardiac Surgery: Past, Present, and Future 
Developing a durable material with the potential to function with child growth will eliminate the need for reoperation and significantly reduce morbidity and mortality in some types of congenital heart defects. Tissue-engineered vascular grafts offer the ability to drastically improve morbidity and mortality and drastically improve the quality of life of patients after congenital heart defect surgery.
In surgical repair for heart or vascular disease, it is often necessary to implant conduits or correct tissue defects. The most commonly used graft materials to date are (a) artificial grafts; (b) autologous tissues, such as pericardium and saphenous vein; (c) allografts; and (d) xenografts. However, none of these four options offer growth potential, and all are associated with varying levels of thrombogenicity and susceptibility to infection. The lack of growth potential of these four options is particularly important in pediatric cardiac surgery, where patients will often outgrow their vascular grafts and require additional operations. Thus, developing a material with sufficient durability and growth potential that will function as the child grows older will eliminate the need for reoperation and significantly reduce morbidity and mortality of some types of congenital heart defects. Vascular tissue engineering is a relatively new field that has undergone enormous growth over the last decade. The goal of vascular tissue engineering is to produce neovessels and neo-organ tissue from autologous cells using a biodegradable polymer as a scaffold. The most important advantage of tissue-engineered implants is that these tissues can grow, remodel, rebuild, and respond to injury. Once the seeded autologous cells have deposited an extracellular matrix and the original scaffold is biodegraded, the tissue resembles and behaves as native tissue. When tissue-engineered vascular grafts are eventually put to use in the clinical arena, the quality of life in patients after surgery will be drastically improved.
PMCID: PMC3659720  PMID: 23197861
Tissue engineering; Stem cells; Cardiac surgery; Congenital heart defects
2.  Telmisartan ameliorates insulin sensitivity by activating the AMPK/SIRT1 pathway in skeletal muscle of obese db/db mice 
Telmisartan is a well-established angiotensin II type 1 receptor blocker that improves insulin sensitivity in animal models of obesity and insulin resistance, as well as in humans. Telmisartan has been reported to function as a partial agonist of the peroxisome proliferator-activated receptor (PPAR) γ, which is also targeted by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase (SIRT1). Here, we investigated the pathways through which telmisartan acts on skeletal muscle, in vitro as well as in vivo.
Nine-week-old male db/db mice were fed a 60% high-fat diet, with orally administrated either vehicle (carboxymethyl-cellulose, CMC), 5 mg/kg telmisartan, or 5 mg/kg telmisartan and 1 mg/kg GW9662, a selective irreversible antagonist of PPARγ, for 5 weeks. Effects of telmisartan on Sirt1 mRNA, AMPK phosphorylation, and NAD+/NADH ratio were determined in C2C12 cultured myocytes.
Results and discussion
Telmisartan treatment improved insulin sensitivity in obese db/db mice fed a high-fat diet and led to reduction in the size of hypertrophic pancreatic islets in these mice. Moreover, in vitro treatment with telmisartan led to increased expression of Sirt1 mRNA in C2C12 skeletal muscle cells; the increase in Sirt1 mRNA in telmisartan-treated C2C12 myoblasts occurred concomitantly with an increase in AMPK phosphorylation, an increase in NAD+/NADH ratio, and increases in the mRNA levels of PGC1α, FATP1, ACO, and GLUT4.
Our results indicate that telmisartan acts through a PPARγ-independent pathway, but at least partially exerts its effects by acting directly on skeletal muscle AMPK/SIRT1 pathways.
PMCID: PMC3527353  PMID: 23137106
Adiponectin; AMP-activated protein kinase; Obesity; Peroxisome proliferator-activated receptor-γ; SIRT1
3.  Gender disparities in the association between epicardial adipose tissue volume and coronary atherosclerosis: A 3-dimensional cardiac computed tomography imaging study in Japanese subjects 
Growing evidence suggests that epicardial adipose tissue (EAT) may contribute to the development of coronary artery disease (CAD). In this study, we explored gender disparities in EAT volume (EATV) and its impact on coronary atherosclerosis.
The study population consisted of 90 consecutive subjects (age: 63 ± 12 years; men: 47, women: 43) who underwent 256-slice multi-detector computed tomography (MDCT) coronary angiography. EATV was measured as the sum of cross-sectional epicardial fat area on CT images, from the lower surface of the left pulmonary artery origin to the apex. Subjects were segregated into the CAD group (coronary luminal narrowing > 50%) and non-CAD group.
EATV/body surface area (BSA) was higher among men in the CAD group than in the non-CAD group (62 ± 13 vs. 33 ± 10 cm3/m2, p < 0.0001), but did not differ significantly among women in the 2 groups (49 ± 18 vs. 42 ± 9 cm3/m2, not significant). Multivariate logistic analysis showed that EATV/BSA was the single predictor for >50% coronary luminal narrowing in men (p < 0.0001). Predictors excluded were age, body mass index, hypertension, diabetes mellitus, and hyperlipidemia.
Increased EATV is strongly associated with coronary atherosclerosis in men.
PMCID: PMC3489699  PMID: 22963346
Atherosclerosis; Gender difference; Epicardial adipose tissue; Obesity
4.  Systemic Preconditioning by a Prolyl Hydroxylase Inhibitor Promotes Prevention of Skin Flap Necrosis via HIF-1-Induced Bone Marrow-Derived Cells 
PLoS ONE  2012;7(8):e42964.
Local skin flaps often present with flap necrosis caused by critical disruption of the blood supply. Although animal studies demonstrate enhanced angiogenesis in ischemic tissue, no strategy for clinical application of this phenomenon has yet been defined. Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in ischemic vascular responses, and its expression is induced by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We assessed whether preoperative stabilization of HIF-1 by systemic introduction of DMOG improves skin flap survival.
Methods and Results
Mice with ischemic skin flaps on the dorsum were treated intraperitoneally with DMOG 48 hr prior to surgery. The surviving area with neovascularization of the ischemic flaps was significantly greater in the DMOG-treated mice. Significantly fewer apoptotic cells were present in the ischemic flaps of DMOG-treated mice. Interestingly, marked increases in circulating endothelial progenitor cells (EPCs) and bone marrow proliferative progenitor cells were observed within 48 hr after DMOG treatment. Furthermore, heterozygous HIF-1α-deficient mice exhibited smaller surviving flap areas, fewer circulating EPCs, and larger numbers of apoptotic cells than did wild-type mice, while DMOG pretreatment of the mutant mice completely restored these parameters. Finally, reconstitution of wild-type mice with the heterozygous deficient bone marrow cells significantly decreased skin flap survival.
We demonstrated that transient activation of the HIF signaling pathway by a single systemic DMOG treatment upregulates not only anti-apoptotic pathways but also enhances neovascularization with concomitant increase in the numbers of bone marrow-derived progenitor cells.
PMCID: PMC3413653  PMID: 22880134
5.  Autologous Peripheral Blood-Derived Mononuclear Cells Induced by Erythropoietin Improve Critical Ischemic Limbs 
Annals of Vascular Diseases  2012;5(1):52-60.
Purpose: Efficient and secure collection of CD34+ cells are crucial for the angiogenic therapies. We have developed autologous peripheral blood-mononuclear cell (MNC) transplantation induced by erythropoietin (rhEPO) for critical ischemic limbs.
Methods: Seven patients, including five with arteriosclerosis obliterans, one with Buerger’s disease and one with progressive systemic sclerosis, underwent ten cell therapies. The first administration of rhEPO was performed two weeks before apheresis, and the second administration and blood donation were performed one week before apheresis to activate bone marrow. MNCs including CD34+ cells, isolated from peripheral blood by apheresis, were immediately injected intramuscularly into ischemic limbs.
Results: The number of peripheral blood-CD34 + cells had significantly increased from 1.32 ± 0.83/microL, before the rhEPO induction, to 1.86 ± 0.94/microL, before the apheresis. The number of transplanted MNCs ranged between 0.5 × 109 and 16.5 × 109, and that of CD34+ cells, between 0.1 × 106 and 12.7 × 106, accounting for 0.02%–0.1% of MNCs. There were no serious complications. Finger ulcers with Buerger’s disease were significantly improved one month after the transplantations, but the same or other ulcer(s) appeared 2–6 months later. Three patients had an improvement in rest pain, and one patient extended maximum pain-free walking distance.
Conclusions: Erythropoietin-induced autologous peripheral blood-MNC transplantation is a useful and safe alternative for ischemic limbs.
PMCID: PMC3595914  PMID: 23555486
Keywordserythropoietin; angiogenesis; autologous peripheral blood-derived mononuclear cell transplantation; critical ischemic limbs

Results 1-5 (5)