Kazuhisa Kondo

Nagoya University, Nagoya, Aichi, Japan

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Publications (18)83.45 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Dipeptidyl peptidase-4 (DPP-4) inhibitors are known to lower glucose levels, and are also beneficial in the management of cardiovascular disease. Here, we investigated whether a DPP-4 inhibitor, vildagliptin, modulates endothelial cell network formation and revascularization processes in vitro and in vivo. Treatment with vildagliptin enhanced blood flow recovery and capillary density in the ischemic limbs of wild-type mice, with accompanying increases in phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In contrast to wild-type mice, treatment with vildagliptin did not improve blood flow in ischemic muscles of eNOS-deficient mice. Treatment with vildagliptin increased the levels of glucagon-like peptide-1 (GLP-1) and adiponectin, which have protective effects on the vasculature. Both vildagliptin and GLP-1 increased the differentiation of cultured human umbilical vein endothelial cells (HUVECs) into vascular-like structures, although vildagliptin was less effective than GLP-1. GLP-1 and vildagliptin also stimulated the phosphorylation of Akt and eNOS in HUVECs. Pretreatment with a PI3-kinase or NOS inhibitor blocked the stimulatory effects of both vildagliptin and GLP-1 on HUVEC differentiation. Furthermore, treatment with vildagliptin only partially increased the limb flow of ischemic muscle in adiponectin-deficient mice in vivo. GLP-1, but not vildagliptin, significantly increased adiponectin expression in differentiated 3T3-L1 adipocytes in vitro. These data indicate that vildagliptin promotes endothelial cell function via eNOS signaling, an effect that may be mediated by both GLP-1-dependent and GLP-1-independent mechanisms. The beneficial activity of GLP-1 for revascularization may also be partially mediated by its ability to increase adiponectin production.
    The Journal of biological chemistry. 08/2014;
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    ABSTRACT: Transplantation of adipose-derived regenerative cell (ADRC) enhances ischemia-induced angiogenesis, but the underlying mechanism remains unknown. Here, we compared the efficacy between ADRC and bone marrow mononuclear cell (BM-MNC) transplantation in rabbits model of hindlimb ischemia, and examined the possible roles of alternative phenotypic macrophages polarization in ADRC-mediated angiogenesis using mice model of hindlimb ischemia. ADRCs and BM-MNCs were isolated from New Zealand White rabbits and C57BL/6J mice. In rabbit studies, our data showed that ADRCs could incorporate into the endothelial vasculature in vitro and in vivo. Both ADRC-conditioned media (CM) and BM-MNC-CM enhanced the migratory ability and interrupted the process of apoptosis in human umbilical vein endothelial cells. Four weeks after cell transplantation, enhanced collateral vessel formation and functional blood flow recovery were observed in the ischemic muscle injected with either ADRCs or BM-MNCs. In mice studies, we presented that ADRCs polarized into the IL-10-releasing M2 macrophages through PGE2-EP2/4 axis and suppressed the expressions of TNF-α and IL-6 in the ischemic muscle. Gene expressions of several angiogenic cytokines were amplified in the macrophages cultured in ADRC-CM rather than BM-MNC-CM. Blockade of IL-10 using neutralizing MAb attenuated the ADRC-mediated angiogenesis and cause muscle apoptosis in vivo. In conclusion, ADRC transplantation harvested similar effect of neovascularization augmentation compared with BM-MNC in experimental rabbit model of hindlimb ischemia; ADRC displayed a unique immunoregulatory manner of accelerating IL-10-releasing M2 macrophages polarization through the PGE2-EP2/4 axis.
    American journal of physiology. Heart and circulatory physiology. 07/2014;
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    ABSTRACT: Adipose-derived regenerative cells (ADRCs) are a promising source of autologous stem cells for regeneration and repair of damaged tissue. Herein, we investigated the therapeutic potential of ADRC sheets created by a magnetite tissue engineering technology (Mag-TE) for myocardial infarction.
    International journal of cardiology. 07/2014;
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    ABSTRACT: Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion (MI/R) injury. No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity following pressure overload-induced hypertrophy. Serum from heart failure patients exhibited significantly decreased nitrosothiol and cGMP levels. TAC was performed in mice at 10-12 weeks of age. Sodium nitrite (50 mg/L) or saline vehicle (VEH) was administered daily in the drinking water post-operative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks post TAC to assess left ventricular dimensions and ejection fraction (LVEF). We observed increased cardiac nitrite, RXNO, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved LVEF and improved LV dimensions) at 9 weeks (p < 0.001 vs. VEH). In addition, circulating and cardiac brain natriuretic peptide (BNP) levels were attenuated in mice receiving nitrite (p < 0.05 vs. VEH). Western blot analyses revealed upregulation of Akt-eNOS-NO-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure. These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.
    Circulation Research 03/2014; · 11.86 Impact Factor
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    ABSTRACT: Previous studies have demonstrated that hydrogen sulfide (H2S) protects against multiple cardiovascular disease states in a similar manner as nitric oxide (NO). H2S therapy also has been shown to augment NO bioavailability and signaling. The purpose of this study was to investigate the impact of H2S deficiency on endothelial NO synthase (eNOS) function, NO production, and ischemia/reperfusion (I/R) injury. We found that mice lacking the H2S-producing enzyme cystathionine γ-lyase (CSE) exhibit elevated oxidative stress, dysfunctional eNOS, diminished NO levels, and exacerbated myocardial and hepatic I/R injury. In CSE KO mice, acute H2S therapy restored eNOS function and NO bioavailability and attenuated I/R injury. In addition, we found that H2S therapy fails to protect against I/R in eNOS phosphomutant mice (S1179A). Our results suggest that H2S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation.
    Proceedings of the National Academy of Sciences 02/2014; · 9.81 Impact Factor
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    ABSTRACT: -Hydrogen sulfide (H2S) has been shown to induce angiogenesis in in vitro models and to promote vessel growth in the setting of hind-limb ischemia. The goal of the present study was to determine the therapeutic potential of a stable, long-acting H2S donor, diallyl trisulfide (DATS), in a model of pressure-overload heart failure and to assess the effects of chronic H2S therapy on myocardial vascular density and angiogenesis. -Transverse aortic constriction (TAC) was performed in mice (C57BL/6J, 8-10 weeks of age). Mice received either vehicle or DATS (200 μg/kg) starting 24 hours after TAC and were followed for 12 weeks using echocardiography. H2S therapy with DATS improved left ventricular remodeling and preserved LV function in the setting of TAC. H2S therapy also increased the expression of the pro-angiogenic factor, vascular endothelial cell growth factor, while decreasing the angiogenesis inhibitor, angiostatin. Further studies revealed that H2S therapy increased the expression of the proliferation marker, Ki67, as well as increased the phosphorylation of endothelial nitric oxide synthase and increased the bioavailability of nitric oxide. Importantly, these changes were associated with an increase in vascular density within the H2S-treated hearts. -These results suggest that H2S therapy attenuates LV remodeling and dysfunction in the setting of heart failure by creating a pro-angiogenic environment for the growth of new vessels.
    Circulation Heart Failure 06/2013; · 6.68 Impact Factor
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    ABSTRACT: BACKGROUND: Cystathionine gamma-lyase (CSE) produces H(2)S via enzymatic conversion of L-cysteine and plays a critical role in cardiovascular homeostasis. We investigated the effects of genetic modulation of CSE and exogenous H(2)S therapy in the setting of pressure overload-induced heart failure. METHODS AND RESULTS: Transverse aortic constriction (TAC) was performed in wild-type (WT), CSE knockout (KO), and cardiac specific CSE transgenic (CS-CSE Tg) mice. In addition, C57BL/6J or CSE KO mice received a novel H(2)S donor (SG-1002). Mice were followed for 12 weeks using echocardiography. We observed a >60% reduction in myocardial and circulating H(2)S levels following TAC. CSE KO mice exhibited cardiac dilatation and dysfunction significantly greater than WT mice following TAC and CS-CSE Tg mice maintained cardiac structure and function following TAC. H(2)S therapy with SG-1002 resulted in cardioprotection during TAC via upregulation of the VEGF-Akt-eNOS-nitric oxide-cGMP pathway with preserved mitochondrial function, attenuated oxidative stress, and increased myocardial vascular density. CONCLUSIONS: Our results demonstrate that H(2)S levels are decreased in mice in the setting of heart failure. Moreover, CSE plays a critical role in the preservation of cardiac function in heart failure and oral H(2)S therapy prevents the transition from compensated to decompensated heart failure in part via upregulation of endothelial nitric oxide synthase (eNOS) and increased NO bioavailability.
    Circulation 02/2013; · 15.20 Impact Factor
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    ABSTRACT: β(2)-adrenoreceptor activation has been shown to protect cardiac myocytes from cell death. We hypothesized that acute β(2)-adrenoreceptor stimulation, using arformoterol (ARF), would attenuate myocardial ischemia/reperfusion (R) injury via NO synthase activation and cause a subsequent increase in NO bioavailability. Male C57BL/6J and endothelial NO synthase (eNOS) knockout mice were subjected to 45 minutes of myocardial ischemia and 24 hours of R. ARF or vehicle was administered 5 minutes before R. Serum troponin-I was measured, and infarct size per area-at-risk was evaluated at 24 hours of R. Echocardiography was performed at baseline and 2 weeks after R. Myocardial cAMP, protein kinase A, eNOS/Akt phosphorylation status, and NO metabolite levels were assayed. ARF (1 µg/kg) reduced infarct size per area-at-risk by 53.1% (P<0.001 versus vehicle) and significantly reduced troponin-I levels (P<0.001 versus vehicle). Ejection fraction was significantly preserved in ARF-treated hearts compared with vehicle hearts at 2 weeks of R. Serum cAMP and nuclear protein kinase A C-α increased 5 and 15 minutes after ARF injection, respectively (P<0.01). ARF increased Akt phosphorylation at Thr(308) (P<0.001) and Ser(473) (P<0.01), and eNOS phosphorylation at Ser(1177) (P<0.01). ARF treatment increased heart nitrosothiol levels (P<0.001) at 15 min after injection. ARF failed to reduce infarct size in eNOS(-/-) mice. Our results indicate that β(2)-adrenoreceptor stimulation activates cAMP, protein kinase A, Akt, and eNOS and augments NO bioavailability. Activation of this prosurvival signaling pathway attenuates myocardial cell death and preserves cardiac function after ischemia/reperfusion.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2012; 32(8):1865-74. · 6.34 Impact Factor
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    ABSTRACT: Diallyl trisulfide (DATS), a polysulfide constituent found in garlic oil, is capable of the release of hydrogen sulfide (H(2)S). H(2)S is a known cardioprotective agent that protects the heart via antioxidant, antiapoptotic, anti-inflammatory, and mitochondrial actions. Here, we investigated DATS as a stable donor of H(2)S during myocardial ischemia-reperfusion (MI/R) injury in vivo. We investigated endogenous H(2)S levels, infarct size, postischemic left ventricular function, mitochondrial respiration and coupling, endothelial nitric oxide (NO) synthase (eNOS) activation, and nuclear E2-related factor (Nrf2) translocation after DATS treatment. Mice were anesthetized and subjected to a surgical model of MI/R injury with and without DATS treatment (200 μg/kg). Both circulating and myocardial H(2)S levels were determined using chemiluminescent gas chromatography. Infarct size was measured after 45 min of ischemia and 24 h of reperfusion. Troponin I release was measured at 2, 4, and 24 h after reperfusion. Cardiac function was measured at baseline and 72 h after reperfusion by echocardiography. Cardiac mitochondria were isolated after MI/R, and mitochondrial respiration was investigated. NO metabolites, eNOS phosphorylation, and Nrf2 translocation were determined 30 min and 2 h after DATS administration. Myocardial H(2)S levels markedly decreased after I/R injury but were rescued by DATS treatment (P < 0.05). DATS administration significantly reduced infarct size per area at risk and per left ventricular area compared with control (P < 0.001) as well as circulating troponin I levels at 4 and 24 h (P < 0.05). Myocardial contractile function was significantly better in DATS-treated hearts compared with vehicle treatment (P < 0.05) 72 h after reperfusion. DATS reduced mitochondrial respiration in a concentration-dependent manner and significantly improved mitochondrial coupling after reperfusion (P < 0.01). DATS activated eNOS (P < 0.05) and increased NO metabolites (P < 0.05). DATS did not appear to significantly induce the Nrf2 pathway. Taken together, these data suggest that DATS is a donor of H(2)S that can be used as a cardioprotective agent to treat MI/R injury.
    AJP Heart and Circulatory Physiology 03/2012; 302(11):H2410-8. · 4.01 Impact Factor
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    ABSTRACT: sulfide and increasing nitric oxide bioavailability myocardium by preservation of endogenous hydrogen The polysulfide diallyl trisulfide protects the ischemic intact animal to the cellular, subcellular, and molecular levels. It is published 12 times a year (monthly) by the American lymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the publishes original investigations on the physiology of the heart, blood vessels, and AJP -Heart
    AJP Heart and Circulatory Physiology 01/2012; · 4.01 Impact Factor
  • Nitric Oxide-biology and Chemistry - NITRIC OXIDE-BIOL CHEM. 01/2011; 24.
  • Kazuhisa Kondo, Shashi Bhushan, David Lefer
    Nitric Oxide-biology and Chemistry - NITRIC OXIDE-BIOL CHEM. 01/2011; 24.
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    ABSTRACT: Adiponectin plays a protective role in the development of obesity-linked disorders. We demonstrated that adiponectin exerts beneficial actions on acute ischemic injury in mice hearts. However, the effects of adiponectin treatment in large animals and its feasibility in clinical practice have not been investigated. This study investigated the effects of intracoronary administration of adiponectin on myocardial ischemia-reperfusion (I/R) injury in pigs. The left anterior descending coronary artery was occluded in pigs for 45 minutes and then reperfused for 24 hours. Recombinant adiponectin protein was given as a bolus intracoronary injection during ischemia. Cardiac functional parameters were measured by a manometer-tipped catheter. Apoptosis was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling staining. Tumor necrosis factor-alpha and interleukin-10 transcripts were analyzed by real-time polymerase chain reaction. Serum levels of derivatives of reactive oxygen metabolites and biological antioxidant potential were measured. Adiponectin protein was determined by immunohistochemical and Western blot analyses. Intracoronary administration of adiponectin protein led to a reduction in myocardial infarct size and improvement of left ventricular function in pigs after I/R. Injected adiponectin protein accumulated in the I/R-injured heart. Adiponectin treatment resulted in decreased tumor necrosis factor-alpha and increased interleukin-10 mRNA levels in the myocardium after I/R. Adiponectin-treated pigs had reduced apoptotic activity in the I/R-injured heart and showed increased biological antioxidant potential levels and decreased derivatives of reactive oxygen metabolite levels in the blood stream after I/R. These data suggest that adiponectin protects against I/R injury in a preclinical pig model through its ability to suppress inflammation, apoptosis, and oxidative stress. Administration of intracoronary adiponectin could be a useful adjunctive therapy for acute myocardial infarction.
    Circulation Cardiovascular Interventions 03/2010; 3(2):166-73. · 6.54 Impact Factor
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    ABSTRACT: Therapeutic angiogenesis is an important means to salvage tissues against severe ischemic diseases in patients with no option for other vascular intervention. A number of recent studies implicated potentials of cell-based therapeutic angiogenesis using autologous bone marrow mononuclear cells, CD34(+) cells, peripheral blood mononuclear cells, and so on. Subcutaneous adipose tissues can be harvested by relatively easy methods. Recent studies indicated that adipose tissues contain progenitor cells or regenerative cells that can give rise to several mesenchymal lineages. Moreover, these progenitor cells can release multiple angiogenic growth factors and cytokines/chomokines including vascular endothelial growth factor (VEGF), hypatocyte growth factor (HGF) and chemokine stromal cell-derived factor-1 (SDF-1). The combination of these biological properties of adipose-derived regenerative cells (ADRCs) implicates that autologous adipose tissue will be a useful cell source for therapeutic angiogenesis in the next generation.
    Current pharmaceutical design 02/2009; 15(24):2784-90. · 4.41 Impact Factor
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    ABSTRACT: Caloric restriction (CR) can extend longevity and modulate the features of obesity-related metabolic and vascular diseases. However, the functional roles of CR in regulation of revascularization in response to ischemia have not been examined. Here we investigated whether CR modulates vascular response by employing a murine hindlimb ischemia model. Wild-type (WT) mice were randomly divided into two groups that were fed either ad libitum (AL) or CR (65% of the diet consumption of AL). Four weeks later, mice were subjected to unilateral hindlimb ischemic surgery. Body weight of WT mice fed CR (CR-WT) was decreased by 26% compared with WT mice fed AL (AL-WT). Revascularization of ischemic hindlimb relative to the contralateral limb was accelerated in CR-WT compared with AL-WT as evaluated by laser Doppler blood flow and capillary density analyses. CR-WT mice had significantly higher plasma levels of the fat-derived hormone adiponectin compared with AL-WT mice. In contrast to WT mice, CR did not affect the revascularization of ischemic limbs of adiponectin-deficient (APN-KO) mice. CR stimulated the phosphorylation of endothelial nitric-oxide synthase (eNOS) in the ischemic limbs of WT mice. CR increased plasma adiponectin levels in eNOS-KO mice but did not stimulate limb perfusion in this strain. CR-WT mice showed enhanced phosphorylation of AMP-activated protein kinase (AMPK) in ischemic muscle, and administration of AMPK inhibitor compound C abolished CR-induced increase in limb perfusion and eNOS phosphorylation in WT mice. Our observations indicate that CR can promote revascularization in response to tissue ischemia via an AMPK-eNOS-dependent mechanism that is mediated by adiponectin.
    Journal of Biological Chemistry 12/2008; 284(3):1718-24. · 4.65 Impact Factor
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    ABSTRACT: Therapeutic angiogenesis using autologous stem/progenitor cells represents a novel strategy for severe ischemic diseases. Recent reports indicated that adipose tissues could supply adipose-derived regenerative cells (ADRCs). Accordingly, we examined whether implantation of ADRCs would augment ischemia-induced angiogenesis. Adipose tissue was obtained from C57BL/6J mice, and ADRCs were isolated using standard methods. ADRCs expressed stromal cell-derived factor 1 (SDF-1) mRNA and proteins. Hind limb ischemia was induced and culture-expanded ADRCs, PBS, or mature adipocytes (MAs) as control cells were injected into the ischemic muscles. At 3 weeks, the ADRC group had a greater laser Doppler blood perfusion index and a higher capillary density compared to the controls. Implantation of ADRCs increased circulating endothelial progenitor cells (EPCs). SDF-1 mRNA abundance at ischemic tissues and serum SDF-1 levels were greater in the ADRC group than in the control group. Finally, intraperitoneal injection of an anti-SDF-1 neutralizing antibody reduced the number of circulating EPCs and therapeutic efficacies of ADRCs. Adipose tissue would be a valuable source for cell-based therapeutic angiogenesis. Moreover, chemokine SDF-1 may play a pivotal role in the ADRCs-mediated angiogenesis at least in part by facilitating mobilization of EPCs.
    Arteriosclerosis Thrombosis and Vascular Biology 11/2008; 29(1):61-6. · 6.34 Impact Factor
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    ABSTRACT: Obesity-linked diseases are associated with suppressed endothelial progenitor cell (EPC) function. Adiponectin is an adipose-derived protein that is downregulated in obese and diabetic subjects. Here, we investigated the effects of adiponectin on EPCs. EPC levels did not increase in adiponectin deficient (APN-KO) in response to hindlimb ischemia. Adenovirus-mediated delivery of adiponectin increased EPC levels in both WT and APN-KO mice. Incubation of human peripheral blood mononuclear cells with adiponectin led to an increase of the number of EPCs. Adiponectin induced EPC differentiation into network structures and served as a chemoattractant in EPC migration assays. These data suggest that hypoadiponectinemia may contribute to the depression of EPC levels that are observed in patients with obesity-related cardiovascular disorders.
    FEBS Letters 06/2008; 582(11):1607-12. · 3.58 Impact Factor
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    ABSTRACT: Background Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is readily metabolized to NO during various pathological states. We have previously demonstrated that sodium nitrite (NaNO2) ameliorates acute myocardial ischemia/reperfusion (MI/R) injury when administered at reperfusion and pretreatment with NaNO2 preconditions the heart against MI/R injury. However, no evidence exists as to whether increasing NO bioavailability via increased NO2 therapy attenuates pressure overload induced heart failure following transverse aortic constriction. Methods and results Transverse aortic constriction (TAC) was performed in male C57/BL6J mice (n = 13 per group) at 10–12 weeks of age. NaNO2 (50 mg/L) or saline vehicle (VEH) was administered daily in the drinking water post-operative day 1 for 9 weeks. Two-dimensional echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks post (TAC) to assess left ventricular dimensions and left ventricular ejection fraction (LVEF). We observed significantly increased circulating and cardiac NO2 and nitrosothiol levels in mice treated with oral NaNO2. NaNO2 (50 mg/L) significantly preserved LVEF and improved left ventricular LV dimensions (LVEDD/LVESD; 3.5/2.2 mm vs. 4.8/4.0 mm, p < 0.001) at 9 weeks when compared to VEH. In addition, circulating brain natriuretic peptide (BNP) levels were significantly (p < 0.05) attenuated in mice receiving NaNO2. Chronic NaNO2 therapy resulted in upregulation of the AKT–eNOS–nitric oxide–cGMP pathway and activation of MEK1/2 ERK pathway along with the attenuation of oxidative stress. Furthermore, in additional studies we observed significant preservation of cardiac function following TAC in cardiac specific eNOS transgenic mice (CS-eNOS Tg) with increased blood and heart NO2 and nitrosothiol levels. Conclusions These results demonstrate that oral NaNO2 therapy or cardiac restricted eNOS gene therapy significantly increases nitrite (NO2) bioavailability, NO bioavailability, and confers significant preservation of cardiac structure and function during heart failure following TAC induced pressure overload. Disclosure Nothing to disclose.
    Nitric Oxide. 31:S30.