Endothelial CLEC-1b plays a protective role against cancer hematogenous metastasis.

Metastasis, which is the spread of cancer cells into distant organs, is a critical determinant of prognosis in patients with cancer, and blood vessels are the major route for cancer cells to spread systemically. Extravasation is a critical process for the hematogenous metastasis; however, its underlying molecular mechanisms remain poorly understood. Here, we identified that senescent ECs highly express C-type lectin domain family 1 member B (CLEC-1b), and that endothelial CLEC-1b inhibits the hematogenous metastasis of a certain type of cancer. CLEC-1b expression was enhanced in ECs isolated from aged mice, senescent cultured human ECs, and ECs of aged human. CLEC-1b overexpression in ECs prevented the disruption of endothelial integrity, and inhibited the transendothelial migration of cancer cells expressing podoplanin (PDPN), a ligand for CLEC-1b. Notably, target activation of CLEC-1b in ECs decreased the hematogenous metastasis in the lungs by cancer cells expressing PDPN in mice. Our data reveal the protective role of endothelial CLEC-1b against cancer hematogenous metastasis. Considering the high CLEC-1b expression in senescent ECs, EC senescence may play a beneficial role with respect to the cancer hematogenous metastasis.

Spermidine improves angiogenic capacity of senescent endothelial cells, and enhances ischemia-induced neovascularization in aged mice.

Aging is closely associated with the increased morbidity and mortality of ischemic cardiovascular disease, at least partially through impaired angiogenic capacity. Endothelial cells (ECs) play a crucial role in angiogenesis, and their angiogenic capacity declines during aging. Spermidine is a naturally occurring polyamine, and its dietary supplementation has exhibited distinct anti-aging and healthy lifespan-extending effects in various species such as yeast, worms, flies, and mice. Here, we explore the effects of spermidine supplementation on the age-related decline in angiogenesis both in vitro and in vivo. Intracellular polyamine contents were reduced in replicative senescent ECs, which were subsequently recovered by spermidine supplementation. Our findings reveal that spermidine supplementation improved the declined angiogenic capacity of senescent ECs, including migration and tube-formation, without affecting the senescence phenotypes. Mechanistically, spermidine enhanced both autophagy and mitophagy, and improved mitochondrial quality in senescent ECs. Ischemia-induced neovascularization was assessed using the hind-limb ischemia model in mice. Limb blood flow recovery and neovascularization in the ischemic muscle were considerably impaired in aged mice compared to young ones. Of note, dietary spermidine significantly enhanced ischemia-induced angiogenesis, and improved the blood flow recovery in the ischemic limb, especially in aged mice. Our results reveal novel proangiogenic functions of spermidine, suggesting its therapeutic potential against ischemic disease.

Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction.

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; (1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, (2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, (3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, (4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

Orotic acid protects pancreatic ß cell by p53 inactivation in diabetic mouse model.

Impairment of pancreatic ß cells is a principal driver of the development of diabetes. Restoring normal insulin release from the ß cells depends on the ATP produced by the intracellular mitochondria. In maintaining mitochondrial function, the tumor suppressor p53 has emerged as a novel regulator of metabolic homeostasis and participates in adaptations to nutritional changes. In this study, we used orotic acid, an intermediate in the pathway for de novo synthesis of the pyrimidine nucleotide, to reduce genotoxicity. Administration of orotic acid reduced p53 activation of MIN6 ß cells and subsequently reduced ß cell death in the db/db mouse. Orotic acid intake helped to maintain the islet size, number of ß cells, and protected insulin secretion in the db/db mouse. In conclusion, orotic acid treatment maintained ß cell function and reduced cell death, and may therefore, be a future therapeutic strategy for the prevention and treatment of diabetes.

Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis.

Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; however, whether and the mechanism by which endothelial cell (EC) senescence is causally implicated in atherosclerosis remains unclear. We here investigate a role of EC senescence in atherosclerosis by utilizing EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 or vascular endothelial cadherin promoter. EC-specific progeria accelerated atherosclerosis in mice with target deletion of ApoE. Mechanistically, senescent ECs were markedly sensitive for inflammation-mediated VCAM-1 induction, leading to enhanced monocyte adhesion. Inhibition of NF-κB signaling abolished the enhanced inflammatory responses in senescent ECs, while NF-κB nuclear translocation in response to TNF-α were similar between young and senescent ECs. We found a higher association of VCAM-1 gene with active histone H3 trimethylated on lysine 4, leading to increased NF-κB accessibility in senescent ECs. Our data revealed that EC cellular senescence causes endothelial hyper-inflammability through epigenetic alteration, which consequently accelerates atherosclerosis. Therefore, EC senescence is a promising therapeutic target for the prevention and/or treatment of atherosclerotic disease in elderly population.

TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension.

Yamanaka R, Hoshino A, Fukai K, Urata R, Minami Y, Honda S, Fushimura Y, Hato D, Iwai-Kanai E, Matoba S. TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension. Am J Physiol Heart Circ Physiol 319: H1087-H1096, 2020. First published September 18, 2020; doi:10.1152/ajpheart.00314.2020.-Pulmonary arterial hypertension (PAH) is a refractory disease. Its prognosis remains poor; hence, establishment of novel therapeutic targets is urgent. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53 and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). Recently, p53 was shown to suppress PAH progression. Because inhibition of autophagy and ROS is known to improve PAH, we examined the effect of TIGAR on PAH progression. We compared pulmonary hypertension (PH) development between TIGAR-deficient knockout (KO) and wild-type (WT) mice using a hypoxia-induced PH model. Human pulmonary artery smooth muscle cells (PASMCs) were used for in vitro experiments with small interfering RNA (siRNA) to investigate the possible molecular mechanisms. From the analysis of right ventricular pressure, right ventricular weight, and mortality rate, we concluded that the hypoxia-induced PH development was remarkably higher in TIGAR KO than in WT mice. Pathological investigation revealed that medial thickening of the pulmonary arterioles and cell proliferation were increased in TIGAR KO mice. Autophagy and ROS activity were also increased in TIGAR KO mice. TIGAR knockdown by siRNA increased cell proliferation and migration, exacerbated autophagy, and increased ROS generation during hypoxia. Autophagy inhibition by chloroquine and ROS inhibition by N-acetylcysteine attenuated the proliferation and migration of PASMCs caused by TIGAR knockdown and hypoxia exposure. TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS and, therefore, improved hypoxia-induced PH. Thus, TIGAR might be a promising therapeutic target for PAH.NEW & NOTEWORTHY Pulmonary arterial hypertension is a refractory disease. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53 and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). By using TIGAR-deficient knockout mice and human pulmonary artery smooth muscle cells, we found that TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS and, therefore, improved hypoxia-induced PH. TIGAR will be a promising therapeutic target for PAH.

Publisher Correction: Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

Successful bailout procedure for acute popliteal artery occlusion associated with EXOSEAL® vascular closure device: a case report.

BACKGROUND: Vascular closure devices have been widely used to achieve rapid hemostasis after percutaneous catheterization procedures via the common femoral artery. The EXOSEAL vascular closure device is a device that can deliver a bioabsorbable polyglycolic acid plug to fill the subcutaneous puncture route at the groin for rapid hemostasis, and this device has a lower risk of arterial occlusion than other vascular closure devices. CASE PRESENTATION: An 83-year-old Japanese man underwent percutaneous coronary intervention for a proximal stenosis in his left circumflex artery through a 7-Fr sheath from his right common femoral artery. We encountered acute popliteal artery occlusion associated with EXOSEAL vascular closure device. We detected the plug material of this device at the occluded lesion by intravascular ultrasound, and performed successful bailout stenting after pulling the embolus with an inflated balloon catheter up to the superficial femoral artery from the popliteal artery. CONCLUSION: Acute limb ischemia caused by an EXOSEAL vascular closure device is a very rare complication. Balloon angioplasty and stenting are considered to be effective options to deal with the plug dislodgement of an EXOSEAL vascular closure device. We must be prepared for every rare complication during endovascular treatment.

A Rare Case of Isolated Idiopathic Inferior Mesenteric Artery Dissection.

BACKGROUND Isolated dissection of a mesenteric artery is very rare and usually presents with acute gastrointestinal symptoms. There have been previously published reports on the isolated dissection of the superior mesenteric artery. However, isolated dissection of the inferior mesenteric artery is rare. CASE REPORT A 43-year-old man presented with sudden onset of lower abdominal pain. Abdominal computed tomography (CT) imaging confirmed isolated dissection of the inferior mesenteric artery. To prevent exacerbation of the dissection, his systolic blood pressure was controlled to <140 mmHg, and his progress was observed for ten days while in hospital during which time the dissection stabilized. There was no extension of the dissection. After three years, the dissection had healed and did not recur. CONCLUSIONS To our knowledge, this is the first case report of isolated dissection of the inferior mesenteric artery that resolved spontaneously. This case shows the importance of blood pressure control in the management of arterial dissection.

Tips of the dual-lumen microcatheter-facilitated reverse wire technique in percutaneous coronary interventions for markedly angulated bifurcated lesions.

In practical settings of percutaneous coronary intervention (PCI), we sometimes encounter difficulty in introducing a guidewire (GW) to the markedly angulated side branch (SB), and the reverse wire technique is considered as a last resort to overcome such a situation. We analyzed 12 cases that underwent PCI with dual-lumen microcatheter-facilitated reverse wire technique between January 2013 and July 2016. We retrospectively investigated the lesion's characteristics and the details of the PCI procedures, and discussed tips about the use of this technique. The SB that exhibits both a smaller take-off angle and a larger carina angle is considered to be the most suitable candidate for this technique. The first step of this technique involves the delivery of the reverse wire system to the target bifurcation. However, most cases exhibit significant stenosis proximal to the bifurcation, which often hampers the delivery of the reverse wire system. Because the sharply curved reverse wire system is easier to pass the stenosis as compared to the roundly curved system, we recommend a sharp curve should be adopted for this technique. On the other hand, it is sure that device delivery is much easier on the GW with a round curve as compared to that with a sharp curve. Therefore, it is important to modify the details of this procedure on a case-by-case basis according to the lesion's characteristics.

Quasi-Phase Diagrams at Air/Oil Interfaces and Bulk Oil Phases for Crystallization of Small-Molecular Semiconductors by Adjusting Gibbs Adsorption.

The temperature and concentration dependencies of the crystallization of two small-molecular semiconductors were clarified by constructing quasi-phase diagrams at air/oil interfaces and in bulk oil phases. A quinoidal quaterthiophene derivative with four alkyl chains (QQT(CN)4) in 1,1,2,2-tetrachroloethane (TCE) and a thienoacene derivative with two alkyl chains (C8-BTBT) in o-dichlorobenzene were used. The apparent crystal nucleation temperature (Tn) and dissolution temperature (Td) of the molecules were determined based on optical microscopy examination in closed glass capillaries and open dishes during slow cooling and heating processes, respectively. Tn and Td were considered estimates of the critical temperatures for nuclear formation and crystal growth, respectively. The Tn values of QQT(CN)4 and C8-BTBT at the air/oil interfaces were higher than those in the bulk oil phases, whereas the Td values at the air/oil interfaces were almost the same as those in the bulk oil phases. These Gibbs adsorption phenomena were attributed to the solvophobic effect of the alkyl chain moieties. The temperature range between Tn and Td corresponds to suitable supercooling conditions for ideal crystal growth based on the suppression of nucleation. The Tn values at the water/oil and oil/glass interfaces did not shift compared with those of the bulk phases, indicating that adsorption did not occur at the hydrophilic interfaces. Promotion and inhibition of nuclear formation for crystal growth of the semiconductors were achieved at the air/oil and hydrophilic interfaces, respectively.

Successful bailout stenting strategy against lethal coronary dissection involving left main bifurcation.

Catheter-induced coronary dissection involving left main bifurcation is a rare complication during cardiac catheterization but can become lethal unless it is treated appropriately. Interventional cardiologists always have to pay attention to the risk of complications related to cardiac catheterization and prepare for determining the best bailout strategy for the situation.

Guide Catheter Extension Device Is Effective in Renal Angioplasty for Severely Calcified Lesions.

BACKGROUND The GuideLiner catheter extension device is a monorail-type "Child" support catheter that facilitates coaxial alignment with the guide catheter and provides an appropriate back-up force. This device has been developed in the field of coronary intervention, and now is becoming widely applied in the field of endovascular treatment. However, there has been no report on the effectiveness of the guide catheter extension device in percutaneous transluminal renal angioplasty (PTRA). CASE REPORT We encountered a case of atherosclerotic subtotal occlusion at the ostium of the left renal artery. Due to the severely calcified orifice and weaker back-up force provided by a JR4 guide catheter, we could not pass any guidewires through the target lesion. Therefore, we introduced a guide catheter extension device, the GuideLiner catheter, through the guide catheter and achieved good guidewire maneuverability. We finally deployed 2 balloon-expandable stents and successfully performed all PTRA procedures. CONCLUSIONS The guide catheter extension device can be effective in PTRA for severely calcified subtotal occlusion.

Instructive percutaneous coronary intervention to avoid the risk of side branch occlusion at a lesion with a lotus root appearance: a case report.

BACKGROUND: A lotus root appearance is a rare entity, and there is little opportunity to perform coronary intervention for this kind of lesion. Because of its peculiar anatomical characteristics, one of the problems regarding percutaneous coronary intervention (PCI) for these lesions is related to the involvement of branch vessels. CASE PRESENTATION: We encountered a case of PCI for a stenotic lesion with a lotus root appearance in the mid-portion of the right coronary artery (RCA). To avoid the risk of right ventricular (RV) branch occlusion due to stent deployment in the main RCA, we re-crossed the third guidewire into the main RCA via the nearest point to the RV branch ostium through the communicating vascular lumen. Thereafter, we deployed a drug-eluting stent in the main RCA crossing over the RV branch, and the ostium of the RV branch remained intact, as we expected. CONCLUSIONS: This case is the first report in the world describing the details of how to maintain the patency of the side branch bifurcating from a lesion with a lotus root appearance under optical coherence tomography guidance.

Trans-collateral angioplasty in vascular access intervention therapy for subacute occluded vessel.

We describe the first reported case of successful trans-collateral angioplasty (TCA) in vascular access intervention therapy (VAIVT) for a subacute occluded lesion in the vascular access route. TCA is a technique which has been developed in the field of endovascular therapy for peripheral arterial disease and is usually applied for a long chronic total occluded lesion with no available distal puncture site. Because such lesion characteristics suitable for being applied with TCA are not usually seen in the patients who receive VAIVT, there is little opportunity when TCA is performed in VAIVT. The present patient showed subacute occlusion in the vascular access route with well-developed collateral blood vessels. Because antegrade wiring resulted in subintimal tracking, we failed to antegradely introduce the guidewire to the vascular true lumen. Moreover, no puncture site in the venous side was anatomically available. Therefore, we adopted the strategy of TCA and successfully completed the procedure. Although we rarely encounter the situation in which TCA is necessary for VAIVT, the strategy of TCA is a promising procedure if the condition permits.

A rare appearance of a large mural thrombus in left atrium detected two years after the Maze procedure.

A 77-year-old Japanese woman underwent bioprosthetic aortic valve replacement (AVR) and the Maze procedure for severe aortic valve disease and paroxysmal atrial fibrillation (AF), and one year after the AVR, she also underwent a permanent pacemaker implantation for sick sinus syndrome. At two postoperative years, a large mural mass happened to be detected in her left atrium on routine trans-thoracic echocardiography. The cardiac rhythm records produced by the implanted pacemaker demonstrated the recurrence of AF. As anticoagulant therapy was not effective at reducing the size of the mass, surgery was performed and organized thrombus was detected on the ablation line made at the Maze procedure. .