Comparison of novel intrinsic versus conventional antitachycardia pacing for ventricular tachycardia among implantable cardioverter-defibrillator recipients.

INTRODUCTION: Intrinsic antitachycardia pacing (iATP) is a novel automated antitachycardia pacing (ATP) that provides individual treatment to terminate ventricular tachycardia (VT). However, the clinical efficacy of iATP in comparison with conventional ATP is unknown. We aim to compare the termination rate of VT between iATP and conventional ATP in patients with implantable cardioverter-defibrillators using a unique setting of different sequential orders of both ATP algorisms. METHODS: Patients with the iATP algorithm were assigned to iATP-first and conventional ATP-first groups sequentially. In the iATP-first group, a maximum of seven iATP sequences were delivered, followed by conventional burst and ramp pacing. In contrast, in the conventional ATP-first group, two bursts and ramp pacing were initially programmed, followed by iATP sequences. We compared the success rates of VT termination in the first and secondary programmed ATP zones between the two groups. RESULTS: Fifty-eight and 56 patients were enrolled in the iATP-first and conventional ATP-first groups, and 67 and 44 VTs were analyzed in each group, respectively. At the first single ATP therapy, success rates were 64% and 70% in the iATP and conventional groups, respectively. At the end of the first iATP treatment zone, the success rate increased from 64% to 85%. Moreover, secondary iATP therapy following the failure of conventional ATPs increased the success rate from 80% to 93%. There was a significant benefit of alternative iATP for VT termination compared to secondary conventional ATP (100% vs. 33%, p = .028). CONCLUSIONS: iATP may be beneficial as a secondary therapy after failure of conventional ATP to terminate VT.

Prognostic impact of polypharmacy and discharge medications in octogenarians and nonagenarian patients with acute heart failure.

With the increasing frequency of heart failure (HF) in elderly patients, polypharmacy has become a major concern owing to its adverse outcomes. However, reports on the clinical impact of polypharmacy and discharge medications in hospitalized super-aged patients with acute HF are rare. Data from 682 patients aged 80 years or older, hospitalized for treating acute HF, were analyzed. We recorded the number of medications at discharge and classified them into three groups: HF, non-HF cardiovascular, and non-cardiovascular medications. We investigated the correlation of polypharmacy, defined as daily administration of 10 or more medications at discharge, and the use of discharge medications with post-discharge prognosis. Polypharmacy was recorded in 24.3% of enrolled patients. Polypharmacy was not an independent predictor of all-cause mortality, the incidence of cardiac-related death, or HF-associated rehospitalization; however, the number of non-cardiovascular medications, multiple usage of potentially inappropriate medications, use of mineralocorticoid receptor antagonists, and doses of loop diuretics were associated with poor prognosis. Polypharmacy was significantly associated with higher mortality in patients with Barthel index ≥ 60 at discharge; hence, physical function at discharge was useful for the stratification of prognostic impacts of polypharmacy. The current study demonstrated that polypharmacy was not essentially associated with poor prognosis in super-aged patients with acute HF. Appropriate medications that consider the patient's physical function, rather than polypharmacy itself, are important for the management of HF.

Omentin Modulates Chronic Cardiac Remodeling After Myocardial Infarction.

Background: Omentin, a circulating adipokine, is downregulated in complications of obesity, including heart disease. Here, we investigated whether omentin modulates adverse cardiac remodeling in mice after myocardial infarction (MI). Methods and Results: Transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg) and wild-type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery (LAD) to induce MI. OMT-Tg mice had a higher survival rate after permanent LAD ligation than WT mice. Moreover, OMT-Tg mice had lower heart weight/body weight (HW/BW) and lung weight/body weight (LW/BW) ratios at 4 weeks after coronary artery ligation compared with WT mice. OMT-Tg mice also showed decreased left ventricular diastolic diameter (LVDd) and increased fractional shortening (%FS) following MI. Moreover, an increase in capillary density in the infarct border zone and a decrease in myocardial apoptosis, myocyte hypertrophy, and interstitial fibrosis in the remote zone following MI, were more prevalent in OMT-Tg than WT mice. Finally, intravenous administration of adenoviral vectors expressing human omentin to WT mice after MI resulted in decreases in HW/BW, LW/BW, and LVDd, and an increase in %FS. Conclusions: Our findings document that human omentin prevents pathological cardiac remodeling after chronic ischemia, suggesting that omentin represents a potential therapeutic molecule for the treatment of ischemic heart disease.

High-grade Endometrial Carcinoma With a Hepatoid Carcinoma-like Component.

Endometrial carcinoma with hepatoid differentiation is rare and <20 reported cases have been reported as endometrial hepatoid carcinoma (EHC). We present a case of EHC associated with serous carcinoma in a 76-yr-old Japanese woman. The hepatoid component showed trabecular, pseudoglandular, and diffuse proliferation of hepatoid cells. The hepatoid cells were positive for α-fetoprotein, Hep-Per-1, glypican 3, and HNF-1ß, weakly and focally positive for SALL4, and negative for PAX8. Both of the serous and hepatoid components showed overexpression of p53. The serum α-fetoprotein on postoperative day 5 was 3691 ng/mL. The postoperative course has remained uneventful for 4 yr. These findings suggested that EHC developed from serous carcinoma by acquiring hepatocytic features and losing Müllerian features. Both serous and hepatoid components showed p53 overexpression, suggesting they share a TP53 mutation as a common primary driver.

Hydrogen Sulfide Attenuates Lymphedema Via the Induction of Lymphangiogenesis Through a PI3K/Akt-Dependent Mechanism.

Background Accumulating evidence suggests that hydrogen sulfide ( H2S ), an endogenously produced gaseous molecule, plays a critical role in the regulation of cardiovascular homeostasis. However, little is known about its role in lymphangiogenesis. Thus, the current study aimed to investigate the involvement of H2S in lymphatic vessel growth and lymphedema resolution using a murine model and assess the underlying mechanisms. Methods and Results A murine model of tail lymphedema was created both in wild-type mice and cystathionine γ-lyase-knockout mice, to evaluate lymphedema up to 28 days after lymphatic ablation. Cystathionine γ-lyase-knockout mice had greater tail diameters than wild-type mice, and this phenomenon was associated with the inhibition of reparative lymphangiogenesis at the site of lymphatic ablation. In contrast, the administration of an H2S donor, diallyl trisulfide, ameliorated lymphedema by inducing the formation of a considerable number of lymphatic vessels at the injured sites in the tails. In vitro experiments using human lymphatic endothelial cells revealed that diallyl trisulfide promoted their proliferation and differentiation into tube-like structures by enhancing Akt (protein kinase B) phosphorylation in a concentration-dependent manner. The blockade of Akt activation negated the diallyl trisulfide-induced prolymphangiogenic responses in lymphatic endothelial cells. Furthermore, the effects of diallyl trisulfide treatment on lymphangiogenesis in the tail lymphedema model were also negated by the inhibition of phosphoinositide 3'-kinase (P13K)/Akt signaling. Conclusions H2S promotes reparative lymphatic vessel growth and ameliorates secondary lymphedema, at least in part, through the activation of the Akt pathway in lymphatic endothelial cells. As such, H2S donors could be used as therapeutics against refractory secondary lymphedema.

Adipose-derived regenerative cells as a promising therapy for cardiovascular diseases: an overview.

The number of patients with ischemic cardiovascular diseases is significantly increasing as populations age. Therapeutic angiogenesis has been developed as a new treatment strategy for such patients. In recent years, the presence of mesenchymal stem cells in adipose tissues was reported, and regenerative medicine using these cells has attracted attention worldwide. In this review, we describe how the transplantation of adipose-derived regenerative cells enhances angiogenesis and tissue regeneration because of their multilineage potential and cytokine secretion. Then, the current status of therapeutic angiogenesis using adipose-derived regenerative cells in the field of cardiovascular medicine was also described. These cells present great advantages over bone marrow mononuclear cells, as these need easier, shorter, and less invasive preparations as well as less ethical concerns and immunological problems. The efficacy of adipose-derived regenerative cell transplantation in the treatment of various diseases was examined in several clinical trials with favorable results. Currently, a multicenter study of therapeutic angiogenesis using these cells is being conducted in patients with critical limb ischemia. In conclusion, we expect that this method will soon be established as a treatment for cardiovascular diseases that have been refractory to conventional treatments.

Evaluation of the Novel Automated Anti-Tachycardia Pacing Algorithm Successfully Terminating Sustained Monomorphic Ventricular Tachycardia in an Electrophysiology Study.

We report the usefulness of novel automated anti-tachycardia pacing (ATP) for ventricular tachycardia (VT) termination evaluated in an electrophysiology study. This intrinsic, automated ATP with an implanted cardiac resynchronization therapy-defibrillator successfully terminated the sustained VT, which had not been suppressed by repetitive burst pacing from the electrode catheter. The reproduction of programed pacing of the automated ATP by a right ventricular electrode catheter was effective in terminating VT, and this termination was absolute and reproducible. Further detailed assessment in an electrophysiology study could highlight the algorithm of the automated ATP and its possible benefit in terminating the reentrant VT.

Impact of synchronized left ventricular pacing rate on risk for ventricular tachyarrhythmias after cardiac resynchronization therapy in patients with heart failure.

BACKGROUND: The adaptive cardiac resynchronization therapy (aCRT) algorithm automatically produces synchronized left ventricular pacing (sLVP) with intrinsic atrioventricular conduction to improve clinical outcomes. However, relationship between sLVP percentage and risk for ventricular tachyarrhythmia (VT/VF) remains unclear. This study aimed to evaluate the clinical impact of sLVP rate on VT/VF occurrence. METHODS: In total, 1,419 device interrogation data from 42 consecutive patients who underwent new aCRT device implantation were retrospectively analyzed. The primary endpoint was the first time VT/VF episode after aCRT device implantation. RESULTS: During a median follow-up of 34 months, 15 patients had VT/VF episodes. Patients were divided into a high sLVP (the average sLVP percentage of ≥ 51.5%, n = 27) or low sLVP group (< 51.5%, n = 15). The high sLVP group had a significantly lower VT/VF incidence (22% vs. 60%; p = 0.014) and an independent predictor for VT/VF occurrence on multivariate analysis (hazard ratio 0.21; p = 0.007). LV ejection fraction improvements after 6 months (12.3 ± 8.7% vs. 2.8 ± 10.3%; p = 0.004) and 12 months (13.8 ± 9.3% vs. 6.2 ± 11.1%; p = 0.030) were significantly greater in the high sLVP group than in the low sLVP group. Age, PR interval, and left atrial diameter were significantly associated with the sLVP rate after aCRT. CONCLUSIONS: Patients with high sLVP percentage after aCRT had lower long-term risk of VT/VF incidence with a favorable response to CRT. A synchronized pacing algorithm using intrinsic conduction may prevent malignant arrhythmias, as well as recover cardiac functions.

Chronic active Epstein-Barr virus infection presenting as refractory chronic sinusitis.

A 44-year-old Japanese man presented with fever and sore throat. He had a history of refractory chronic sinusitis that did not respond to several years of pharmacotherapy, and underwent endoscopic sinus surgery (ESS) 5 months prior to his presentation, but his symptoms persisted. A biopsy specimen was taken from the right nasal cavity, and extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) was diagnosed. Two years after complete remission was achieved by chemoradiation therapy, he developed hemophagocytic lymphohistiocytosis (HLH) without recurrence of ENKTL. Epstein-Barr virus (EBV)-DNA copy number was relatively high and EBV-infected lymphocytes (CD8 + T cells) were detected in the peripheral blood. Pathological review of the biopsy specimens taken during ESS showed that CD8 + T cells with slightly atypia infiltrating the stroma were EBV positive. These findings suggested that the patient had underlying chronic active EBV infection (CAEBV) that caused the refractory chronic sinusitis, eventually developed into ENKTL, and also caused HLH. Clinicians should consider adult-onset CAEBV in the differential diagnosis of patients with refractory chronic sinusitis.

Zinc deficiency impairs ischemia-induced angiogenesis.

OBJECTIVE: Zinc is an important essential trace metal involved in many physiologic functions, and its deficiency can affect the development of multiple organs, including the vasculature. However, clarity is lacking regarding the effects of zinc deficiency in the regulation of angiogenesis. We investigated the effects of zinc deficiency on the revascularization process through animal experiments and examined the relationship between the circulating zinc levels and tissue blood perfusion in patients with chronic limb-threatening ischemia (CLTI). METHODS: Zinc-deficient mice and control wild-type mice had undergone surgery to create unilateral hindlimb ischemia. Next, we examined the relationship between the serum zinc levels and skin perfusion pressure (SPP) as an index of tissue blood perfusion in patients with CLTI. A total of 51 patients with CLTI who had been referred for de novo revascularization for CLTI due to arteriosclerosis obliterans at our hospital from May 2012 to March 2016 were enrolled. RESULTS: The zinc-deficient mice showed a significant reduction in blood flow recovery rates in the ischemic limb and capillary density in the ischemic adductor muscle fibers compared with the control wild-type mice. The zinc-deficient mice also showed increased reactive oxygen species production after hindlimb ischemia. Nicotinamide adenine dinucleotide phosphate oxidase inhibitors ameliorated the zinc deficient-induced impairment of revascularization. The serum zinc levels were positively associated with the SPP in the CLTI patients. Multivariate regression analysis also revealed that the serum zinc levels were significantly correlated with the SPP in patients with CLTI. CONCLUSIONS: Zinc deficiency impaired the rate of ischemia-induced revascularization through enhanced oxidative stress rates, suggesting that nutritional management for zinc sufficiency could be useful in CLTI prevention and treatment.

Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice.

AIMS: Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice. METHODS AND RESULTS: apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflammatory genes in aortic walls compared with apoE-KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibres in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide. Treatment of human vascular smooth muscle cells (VSMCs) with omentin protein reduced expression and activation of MMP2 after stimulation with tumour necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and VSMCs. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVß3/PI3-kinase/Akt signalling in macrophages and VSMCs, respectively. CONCLUSION: These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.

Transformed diffuse large B-cell lymphoma from marginal zone lymphoma in the anterior mediastinum: A case report and review of the literature.

Marginal zone lymphoma (MZL) arising from the anterior mediastinum is rare. In the majority of reported cases, the tumor was incidentally discovered, reflecting its indolent clinical features. We present a 38-year-old woman who had no medical history, and presented with a bulky anterior mediastinal tumor complicated by life-threatening compression of the vasculature and bronchi. Biopsy specimens of the neoplasm suggested transformed diffuse large B-cell lymphoma (DLBCL) from MZL. To our best knowledge, this is the first case report of anterior mediastinum MZL associated with an aggressive clinical course and life-threatening complications likely due to transformation to DLBCL.

Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia.

Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (P<0.05). The jet-lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next, Cry1 and Cry2 double-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double-knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

A Case of Metastatic Fumarate Hydratase-Deficient-like Renal Cell Carcinoma Successfully Managed by Ipilimumab plus Nivolumab.

We report a 62-year-old male with metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) without fumarate hydratase (FH) mutation (FH-deficient-like RCC). The International Metastatic RCC Database Consortium risk score was intermediate, and immunotherapy with nivolumab and ipilimumab (Ipi/ Nivo) was initiated. Four cycles of Ipi/Nivo and 5 cycles of nivolumab resulted in a complete response of the metastases. Hypophysitis occurred as an immune-related adverse event after four cycles of Ipi/Nivo. The prognosis of patients with FH-deficient RCC is generally poor. Few reports of FH-deficient RCC successfully treated with Ipi/Nivo have been published. Ipi/Nivo can be effective for treating FH-deficient RCC.

Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by tissue fibrosis and intense lymphoplasmacytic infiltration, causing progressive organ dysfunction. Activation-induced cytidine deaminase (AID), a deaminase normally expressed in activated B-cells in germinal centers, edits ribonucleotides to induce somatic hypermutation and class switching of immunoglobulin. While AID expression is strictly controlled under physiological conditions, chronic inflammation has been noted to induce its upregulation to propel oncogenesis. We examined AID expression in IgG4-related ophthalmic disease (IgG4-ROD; n = 16), marginal zone lymphoma with IgG4-positive cells (IgG4+ MZL; n = 11), and marginal zone lymphoma without IgG4-positive cells (IgG4- MZL; n = 12) of ocular adnexa using immunohistochemical staining. Immunohistochemistry revealed significantly higher AID-intensity index in IgG4-ROD and IgG4+ MZL than IgG4- MZL (p < 0.001 and = 0.001, respectively). The present results suggest that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation, and AID may be a driver of oncogenesis in IgG4-ROD to IgG4+ MZL.

Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia.

[Figure: see text].

Intramyocardial Transplantation of Human iPS Cell-Derived Cardiac Spheroids Improves Cardiac Function in Heart Failure Animals.

The severe shortage of donor hearts hampered the cardiac transplantation to patients with advanced heart failure. Therefore, cardiac regenerative therapies are eagerly awaited as a substitution. Human induced pluripotent stem cells (hiPSCs) are realistic cell source for regenerative cardiomyocytes. The hiPSC-derived cardiomyocytes are highly expected to help the recovery of heart. Avoidance of teratoma formation and large-scale culture of cardiomyocytes are definitely necessary for clinical setting. The combination of pure cardiac spheroids and gelatin hydrogel succeeded to recover reduced ejection fraction. The feasible transplantation strategy including transplantation device for regenerative cardiomyocytes are established in this study.

No influence on tumor growth by intramuscular injection of adipose-derived regenerative cells: safety evaluation of therapeutic angiogenesis with cell therapy.

Therapeutic angiogenesis with autologous stem/progenitor cells is a promising novel strategy for treatment of severe ischemic diseases. Human clinical trials utilizing autologous adipose-derived regenerative cells (ADRCs) have not reported treatment-related critical adverse effects thus far. However, there is still a large knowledge gap regarding whether treatment of ischemic diseases with angiogenic therapy using ADRCs would promote unfavorable angiogenesis associated with tumors in vivo. Herein, we addressed this clinical question using a mouse hindlimb ischemia (HLI) and simultaneous remote tumor implantation model. C57BL/6J background wild-type mice were injected with murine B16F10 melanoma cells on their back, 1 day before ischemic surgery. These mice were subjected to surgical unilateral hindlimb ischemia, followed by ADRC implantation or PBS injection into the hindlimb ischemic muscles on the next day. Intramuscular implantation of ADRCs enhanced tissue capillary density and blood flow examined by a laser Doppler blood perfusion analysis in hind limb. However, this therapeutic regimen for ischemic limb using ADRCs did not affect remote melanoma growth nor the density of its feeder artery, angiogenesis, and lymphatic vessels compared with the PBS group. In addition, no distant metastases were detected in any of the mice regardless of the group. In conclusion, local implantation of ADRCs promotes angiogenesis in response to tissue ischemia in the hindlimb without promoting remote tumor growth and related angio/lymphangiogenesis. Therapeutic angiogenesis to the ischemic hindlimb using ADRCs seems to be safe regarding remote tumor growth.NEW & NOTEWORTHY In this study, we demonstrated that local injection of ADRCs can promote angiogenesis in response to tissue ischemia without promoting remote tumor growth in a mouse model. Our findings indicate that therapeutic angiogenesis to the ischemic hindlimb using ADRCs seems to be safe regarding remote tumor growth.

Therapeutic angiogenesis using autologous adipose-derived regenerative cells in patients with critical limb ischaemia in Japan: a clinical pilot study.

Adipose-derived regenerative cell (ADRC) is a promising alternative source of autologous somatic stem cells for the repair of damaged tissue. This study aimed to assess the safety and feasibility of autologous ADRC implantation for therapeutic angiogenesis in patients with critical limb ischaemia (CLI). A clinical pilot study-Therapeutic Angiogenesis by Cell Transplantation using ADRCs (TACT-ADRC) study-was initiated in Japan. Adipose tissue was obtained by ordinary liposuction method. Isolated ADRCs were injected into the ischaemic limb. We performed TACT-ADRC procedure in five patients with CLI. At 6 months, no adverse events related to the TACT-ADRC were observed. No patients required major limb amputation, and ischaemic ulcers were partly or completely healed during the 6-month follow-up. In all cases, significant clinical improvements were seen in terms of rest pain and 6-min walking distance. Numbers of circulating CD34+ and CD133+ cells markers of progenitor cell persistently increased after ADRC implantation. The ratio of VEGF-A165b (an anti-angiogenic isoform of VEGF) to total VEGF-A in plasma significantly decreased after ADRC implantation. In vitro experiments, cultured with ADRC-conditioned media (CM) resulted in increased total VEGF-A and decreased VEGF-A165b in C2C12 cells, but not in macrophages. ADRC-CM also increased CD206+ cells expression and decreased TNF-α in macrophages. Autologous ADRC implantation was safe and effective in patients with CLI and could repair damaged tissue via its ability to promote angiogenesis and suppress tissue inflammation.

C1q/TNF-Related Protein 9 Promotes Revascularization in Response to Ischemia via an eNOS-Dependent Manner.

Strategies to promote revascularization are valuable for ischemic cardiovascular disease. Although C1q/TNF-related protein (CTRP) 9 is an adiponectin paralog with protective properties against cardiometabolic disorders, the role of endogenous CTRP9 in endothelial function is largely unknown. This study aimed to investigate the effects of CTRP9 on revascularization processes and dissected the potential mechanisms. CTRP9-knockout (KO) and wild-type (WT) mice were subjected to unilateral hindlimb ischemic surgery. CTRP9-KO mice exhibited impaired blood flow recovery and decreased capillary density in the ischemic limb compared with WT mice. In both CTRP9-KO and WT mice, systemic delivery of an adenoviral vector expressing CTRP9 (Ad-CTRP9) accelerated blood flow recovery. Treatment with recombinant CTRP9 protein increased network formation and migration of cultured human umbilical vein endothelial cells (HUVECs). CTRP9 promoted the phosphorylation of AMP-activated kinase (AMPK), Akt, and endothelial nitric oxide synthase (eNOS) in HUVECs. CTRP9-KO mice also showed reduced phosphorylation levels of AMPK, Akt, and eNOS in the ischemic limbs compared with WT mice. Furthermore, blockade of AMPK or Akt signaling pathway reversed the CTRP9-stimulated eNOS phosphorylation in HUVECs. Treatment with the NOS inhibitor significantly reduced CTRP9-stimulated network formation and migration of HUVECs. Of note, Ad-CTRP9 had no effects on blood flow of the ischemic limb in eNOS-KO mice. These results indicated that CTRP9 promotes endothelial cell function and ischemia-induced revascularization through the eNOS-dependent mechanism, suggesting that CTRP9 represents a target molecule for treatment of ischemic vascular diseases.