Adenovirus-mediated delivery of Fas ligand inhibits intimal hyperplasia following balloon injury in immunologically-primed animals

Adenoviral constructs have been used for studies of injury-induced vascular hyperplasia in immunologically naive laboratory animals, but their usefulness for intra-arterial gene therapy may be limited by the prevalence of preexisting immunity to adenovirus in the patient population. Here, we explored the efficacy of adenovirus-mediated transfer of Fas ligand, a cytotoxic gene with immunomodulatory properties, in inhibiting injury-induced vascular lesion formation in both naive and immunologically primed animals. Lesion formation was evaluated in balloon-injured carotid arteries of naive and adenovirus-immunized rats that were infected with adenoviral constructs expressing Fas ligand (Ad-FasL), the cyclin-dependent kinase inhibitor p21 (Ad-p21), or beta-galactosidase (Ad-betagal). In naive rats, Ad-FasL induced apoptosis in medial vascular smooth muscle cells and inhibited intimal hyperplasia by 60% relative to Ad-betagal-treated vessels (P<0.05), whereas the cytostatic agent Ad-p21 decreased lesion size by 58% (P<0.05). In animals preimmunized with an adenoviral vector containing no transgene, Ad-FasL significantly inhibited neointima formation (73% reduction, P<0.05), but Ad-p21 failed to inhibit neointima formation relative to controls. Immunologically primed rats displayed robust T-cell infiltration in Ad-p21- and Ad-betagal-treated vessels, but T-cell infiltration was markedly attenuated in Ad-FasL-treated vessels. Our data demonstrate that adenovirus-mediated Fas ligand delivery can inhibit intimal hyperplasia in both immunologically primed and naive animals, whereas the efficacy of an adenovirus-mediated p21 delivery is limited to immunologically naive animals. This study documents, for the first time, the therapeutic efficacy of intravascular adenoviral gene transfer in animals with preexisting immunity to adenovirus.


Fas/Apo [Apoptosis]-1 and associated proteins in the differentiating cerebral cortex: Induction of caspase dependent cell death and activation of NF-κB

The developing cerebral cortex undergoes a period of substantial cell death. The present studies examine the role of the suicide receptor Fas/Apo[apoptosis]-1 in cerebral cortical development. Fas mRNA and protein are transiently expressed in subsets of cells within the developing rat cerebral cortex during the peak period of apoptosis. Fas-immunoreactive cells were localized in close proximity to Fas ligand (FasL)-expressing cells. The Fas-associated signaling protein receptor interacting protein (RIP) was expressed by some Fas-expressing cells, whereas Fas-associated death domain (FADD) was undetectable in the early postnatal cerebral cortex. FLICE-inhibitory protein (FLIP), an inhibitor of Fas activation, was also expressed in the postnatal cerebral cortex. Fas expression was more ubiquitous in embryonic cortical neuroblasts in dissociated culture compared to in situ within the developing brain, suggesting that the environmental milieu partly suppresses Fas expression at this developmental stage. Furthermore, FADD, RIP, and FLIP were also expressed by subsets of dissociated cortical neuroblasts in culture. Fas activation by ligand (FasL) or anti-Fas antibody induced caspase-dependent cell death in primary embryonic cortical neuroblast cultures. The activation of Fas was also accompanied by a rapid downregulation of Fas receptor expression, non-cell cycle-related incorporation of nucleic acids and nuclear translocation of the RelA/p65 subunit of the transcription factor NF-kappaB. Together, these data suggest that adult cortical cell number may be established, in part, by an active process of receptor-mediated cell suicide, initiated in situ by killer (FasL-expressing) cells and that Fas may have functions in addition to suicide in the developing brain.


Effect of inhaled nitric oxide on gas exchange in patients with congestive heart failure. A randomized,controlled trial


Endothelial cell apoptosis induced by oxidized LDL is associated with the downregulation of the cellular caspase inhibitor FLIP


Oxidized LDL activates Fas-mediated endothelial cell apoptosis


Bax-mediated cell death by the Gax homeoprotein requires mitogen-activation but is independent of cell cycle activity


TNFα regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation

It is generally believed that the vascular endothelium serves as an inflammatory barrier by providing a nonadherent surface to leukocytes. Here, we report that Fas ligand (FasL) is expressed on vascular endothelial cells (ECs) and that it may function to actively inhibit leukocyte extravasation. TNFalpha downregulates FasL expression with an accompanying decrease in EC cytotoxicity toward co-cultured Fas-bearing cells. Local administration of TNFalpha to arteries downregulates endothelial FasL expression and induces mononuclear cell infiltration. Constitutive FasL expression markedly attenuates TNFalpha-induced cell infiltration and adherent mononuclear cells undergo apoptosis under these conditions. These findings suggest that endothelial FasL expression can negatively regulate leukocyte extravasation.


Fas ligand gene transfer to the vessel wall inhibits neointima formation and overrides the adenovirus-mediated T cell response

Proceedings of the National Academy of Sciences of the United States of America


A hinge at the central helix of the regulatory light chain of myosin is critical for phosphrylation-dependent regulation of smooth muscle myosin motor activity


The motor domain and the regulatory domain of myosin solely dictate enzymatic activity and phosphorylation dependent regulation, respectively


Functional analysis of the mutations in the human cardiac β-myosin that are responsible for familial hypertrophic cardiomyopathy: Implication for the clinical outcome


Characterization of the motor and enzymatic properties of smooth muscle long S1 and short HMM: Role of the two headed structure on the activity and regulation of myosin motor


Functional expression of mammalian myosin Iβ: Analysis of its motor activity


Coupling between myosin ATPase cycle and creatine kinase cycle facilitates cardiac actomyosin sliding in vitro: A clue to mechanical dysfunction during myocardial ischemia


Force-velocity relations of rat cardiac myosin isozymes sliding on algal actin cables in vitro


Effects of exercise on plasma level of brain natriuretic peptide in congestive heart failure with and without left ventricular dysfunction


Pimobendan directly sensitizes reconstituted thin filament sliding on cardiac myosin


MCI-154 increases Ca2+ sensitivity of reconstituted thin filament. A study using a novel in vitro motility assay technique


A new in vitro motility assay technique to evaluate calcium sensitivity of the cardiac contractile proteins

Pflügers Archiv : European Journal of Physiology


Increased nitric oxide production during exercise


ADP inhibits the slidingvelocity of fluorescent actin filaments on cardiac and skeletal myosins


Dynamic interaction between cardiac myosin isoforms modifies velocity of actomyosin sliding in vitro.


Depressed sliding velocity of isolated cardiac myosin from cardiomypathic hamsters: evidence for an alteration in mechanical interaction of actomyosin


Dynamic left ventricular outflow tract obstruction 4 years after aortic valve replacement.


A case of membranous nephropathy complicated by interstitial nephritis due to Sjogren's syndrome


術前の画像検査で肝細胞癌と診断された肝炎症性偽腫瘍の1例

術前の画像検査で肝細胞癌と診断された肝炎症性偽腫瘍の1例

症例は70代,男性.近医の定期的な血液検査で胆道系酵素の上昇を認めたため,腹部超音波検査を施行したところ,肝左葉内側区に腫瘤を認めた.当院消化器外科に紹介となり,肝内側区切除術が施行され,肝細胞癌と診断された.術後7ヵ月,当院で経過観察目的に施行した造影CT検査で肝左葉外側区に新たに腫瘤を認め,再度精査となった.血液検査では,γ-GTPの軽度上昇を認めるのみで,腫瘍マーカーの上昇は認めなかった.術前の精査目的に施行した腹部超音波検査では,肝左葉外側区(S2)に18×16mm大の腫瘤を認めた.境界明瞭,輪郭は後面が整,前面がやや不整,内部エコーは等輝度で不均質であった.辺縁に比較的厚い低エコー帯を伴っていた.心拍動の影響で血流シグナルの評価は困難であった.腹部造影CT検査では,肝左葉外側区(S2)に2cm大の腫瘤を認め,早期濃染および洗い出しが確認された.本症例は,術前の超音波検査で,肝細胞癌としては非典型的な像を呈していたが,他の画像所見および既往歴から肝細胞癌の再発が否定できず,肝部分切除術が施行され,肝炎症性偽腫瘍と診断された.本症例のように肝細胞癌のリスクが高い症例においても,新規に腫瘤を認めた際には,超音波検査でその特徴を注意深く観察し,典型像と異なる場合には肝炎症性偽腫瘍も鑑別疾患の一つとして考慮した方がよいと考える.(著者抄録)

Japanese Journal of Medical Ultrasound Technology


Optimizing antihypertensive therapy in patients with diabetes mellitus


YS-1402皮下投与および心筋投与における虚血性心筋症に対する効果の検討

YS-1402皮下投与および心筋投与における虚血性心筋症に対する効果の検討

月刊バイオインダストリー


動脈硬化診療のすべて A.成因:基礎研究，日本医師会雑誌 生涯教育シリーズ-97 磯部光章他監修・編集


EPA・DHAと心血管疾患

EPA・DHAと心血管疾患


Minimal shortening of leukocyte telomere length across age groups in a cross-sectional study for carriers of a longevity-associated FOXO3 allele.

FOXO3 is one of the most prominent genes demonstrating a consistently reproducible genetic association with human longevity. The mechanisms by which these individual gene variants confer greater organismal lifespan are not well understood. We assessed the effect of longevity-associated FOXO3 alleles on age-related leukocyte telomere dynamics in a cross-sectional study comprised of samples from 121 healthy Okinawan-Japanese donors aged 21-95 years. We found that telomere length for carriers of the longevity associated allele of FOXO3 single nucleotide polymorphism rs2802292 displayed no significant correlation with age, an effect that was most pronounced in older (>50 years of age) participants. This is the first validated longevity gene variant identified to date showing an association with negligible loss of telomere length with age in humans in a cross-sectional study. Reduced telomere attrition may be a key mechanism for the longevity-promoting effect of the FOXO3 genotype studied.

The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences


(巻頭言) 特集 心筋梗塞から身を守る-発作が起こる前と起こってからできること-


血管保護をふまえた脂質異常症の薬物治療

血管保護をふまえた脂質異常症の薬物治療


待たれる脂肪入れ替え術の臨床試験

待たれる脂肪入れ替え術の臨床試験


狭心症の薬物療法 スタチンに関する最近の話題―strong statinとvascular statinをどのように選択するのか?


Long-term endothelial dysfunction after coronary artery stenting with drug-eluting stent associated with local inflammatory response.


Local hypercoagulability and endothelial dysfunction after sirolimus-eluting stent implantation: implication for late stent thrombosis.


Long-term local inflammatory response after coronary artery stenting with drug-eluting stent.


Message From the Editor-in-Chief Circulation Reports: 4 Years of Progress After Launch


Preload Stress Echocardiography for the Assessment of Heart Failure With Preserved Ejection Fraction


Identifying the extent of oral fluid droplets on echocardiographic machine consoles in COVID-19 era


Effects of Transthoracic Echocardiographic Simulator Training on Performance and Satisfaction in Medical Students.

Journal of the American Society of Echocardiography