Hai-Yan Pan

Nantong University, Tungchow, Jiangsu Sheng, China

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Publications (10)23.12 Total impact

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    ABSTRACT: We previously reported ectopic trypsin in the myocardium triggers acute myocarditis after influenza A virus (IAV) infection. As myocarditis is a common precursor to dilated cardiomyopathy (DCM), the aim of this study was to investigate the influence of trypsin on progression of DCM after IAV infection. IAV-infected mice treated with saline or trypsin inhibitor were euthanized at day 0, 9, 20, 40 and 60 post infection. Trypsin expression colocalized with myocardial inflammatory loci and IAV-induced myocarditis peaked at day 9 post infection and alleviated by day 20, but persisted until day 60 post infection, even though replication of IAV was not detected from day 20 post infection. Similar time courses were observed for activation of promatrix metalloproteinase (proMMP)-9 and expression of proinflammatory cytokines interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α. Degradation of collagen I (Col I), proliferation of ventricular interstitial collagen and expression of Col I and Col III mRNA increased significantly during acute and chronic phases; Col III mRNA increased more significantly than Col I mRNA. Cardiac function progressively deteriorated with progressive left ventricular dilation. The trypsin inhibitor aprotinin suppressed proMMP-9 activation and cytokine release, alleviated myocardial inflammation and restored collagen metabolism during acute and chronic phases of myocarditis. This effectively prevented ventricular dilation and improved cardiac function. These results suggested ectopic trypsin in the myocardium promoted DCM through chronic activation of proMMP-9, persistent induction of cytokines and mediation of collagen remodeling. Pharmacologic inhibition of trypsin activity might be a promising approach for prevention of viral cardiomyopathy.
    AJP Heart and Circulatory Physiology 07/2014; 307(6). DOI:10.1152/ajpheart.00076.2014 · 4.01 Impact Factor
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    ABSTRACT: Recombinant human B-type natriuretic peptide (rhBNP) has been indicated for the treatment of acute decompensated heart failure (ADHF). However, the therapeutic efficacy of intravenous rhBNP is not always satisfactory in patients with extremely high blood BNP levels. In this study, we evaluated the effects of rhBNP on patients with different BNP levels. One hundred and five patients with ADHF whose left ventricular ejection fraction (LVEF) was <40%, were assigned to a high BNP group (BNP <= 3000 pg/mL) or an extra-high BNP group (BNP > 3000 pg/mL) , depending on their admission plasma BNP levels. Each group was then subdivided into rhBNP or dobutamine subgroups according to intravenous administration with either rhBNP or dobutamine for 24-72h. In the high BNP group, 58 patients were randomized to subgroup rhBNP (n = 28) and subgroup dobutamine(n = 30). In the extra-high BNP group, 47 patients were randomized to subgroup rhBNP (n = 24) and subgroup dobutamine (n = 23). The effects of rhBNP and dobutamine on patients in the high and extra-high BNP groups were compared. In the high BNP group, rhBNP was more efficient than dobutamine at improving NYHA classification (P < 0.05), decreasing plasma BNP levels (P < 0.05), increasing LVEF (P < 0.05), and reducing hospital length of stay (P < 0.05). However, rhBNP displayed no superior therapeutic efficacy to dobutamine in the extra-high BNP group. Adverse cardiovascular events in patients treated with rhBNP were similar to adverse events in patients treated with dobutamine in both the high and extra-high BNP groups. rhBNP was more efficient than dobutamine at improving heart function in patients with ADHF when plasma BNP was <=3000 pg/mL. However, rhBNP treatment showed no advantages over dobutamine when plasma BNP reached extremely high levels (>3000 pg/mL).Trial registration: ClinicalTrials.gov Identifier: NCT01837849.
    BMC Cardiovascular Disorders 03/2014; 14(1):31. DOI:10.1186/1471-2261-14-31 · 1.50 Impact Factor
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    ABSTRACT: There is an accumulating body of evidence indicating strong association between inflammation and the pathogenesis of atrial fibrillation (AF). IL-10 is a multifunctional anti-inflammatory cytokine that down-regulates cell-mediated immune responses and cytotoxic inflammatory responses. The aim of the present study is to investigate the association of IL-10 gene -592A/C polymorphism with AF in Han Chinese. 117 AF patients and 100 healthy volunteers were eligible for this study. The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-10 -592A/C genotypes (AA, AC, and CC) was 55.00%, 35.00%, and 10.00% in the controls, and 71.79%, 23.08%, and 5.13% in AF subjects, respectively (p = 0.0335). The frequency of the A allele in the AF group was significantly higher than that in the control group (83.33% vs 72.50%, p = 0.0063). Compared with the CC genotype, the AA genotype had increased risk of AF in both unadjusted and adjusted analyses. The average serum IL-10 levels in AA genotype were statistically lower than in AC + CC genotype (p = 0.0000). These findings suggest that IL-10 -592A/C polymorphism is associated with AF and the A allele has increased risk for AF in Han Chinese.
    International Journal of Clinical and Experimental Medicine 01/2014; 7(11):4199-206. · 1.42 Impact Factor
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    ABSTRACT: There is an accumulating body of evidence indicating association between inflammation and the pathogenesis of coronary vasospastic angina (CVA). Interleukin-6 (IL-6) is a pleiotropic cytokine, functions as a mediator of inflammatory response and has both pro-inflammatory and anti-inflammatory properties. The aim of the present study is to investigate the association of -634C/G polymorphism of IL-6 gene with CVA in Han Chinese. A total of 27 CVA patients and 232 healthy controls were eligible for this study. The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-6 -634C/G genotypes (CC, CG, and GG) was 59.48%, 37.07%, and 3.45% in the controls, and 37.04%, 48.15%, and 14.81% in CVA group, respectively (P = 0.0080). The frequency of the G allele in the CVA group was significantly higher than that in the control group (38.89% vs 21.98%, P = 0.0057). Compared with the wild type CC, the G allele carriers (CG + GG genotypes) had increased risk of CVA in both unadjusted and adjusted analyses. These findings suggest that IL-6 -634C/G polymorphism is associated with CVA and the G allele is an independent risk for CVA in Han Chinese.
    International Journal of Clinical and Experimental Medicine 01/2014; 7(9):2858-64. · 1.42 Impact Factor
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    ABSTRACT: Inflammation has been shown to be implicated in the pathophysiology of atrial fibrillation (AF). Interleukin-6 (IL-6) is a pleiotropic cytokine, functions as a mediator of inflammatory response and has both pro-inflammatory and anti-inflammatory properties. Little is known about genetic factors of inflammation in the accompanying atrial electrical remodeling expressed by P wave dispersion (Pdisp). The aim of the present study is to evaluate the association of -634C/G polymorphism of IL-6 gene with Pdisp in Han Chinese hypertensive patients with AF. A total of 100 patients with essential hypertension (EH) were eligible for this study. Patients with paroxysmal AF (n=50) were allocated to the AF group, and 50 subjects without AF to the control group. The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-6 -634C/G genotypes (CC, CG, and GG) was 68.00%, 28.00%, and 4.00% in the controls, and 44.00%, 40.00%, and 16.00% in AF subjects, respectively (P=0.0269). The frequency of the G allele in the AF group was significantly higher than that in the control group (36.00% vs 18.00%, P=0.0041). Compared to the wild type CC, the G allele carriers (CG + GG genotypes) had a 2.7045-fold increased risk of AF (odds ratio =2.7045, 95% confidence interval =1.1966-6.1126, P=0.0156). AF patients with the CG + GG genotype had longer Pdisp (P=0.0032) than did patients with the CC genotype. The longer Pdisp in the subjects with the CG + GG genotype was also found in the control group (P=0.0016). These findings support that IL-6 -634C/G polymorphism is associated with Pdisp and AF, suggesting an active implication of inflammation in the atrial electrophysiological remodeling predisposing to AF.
    International Journal of Clinical and Experimental Medicine 01/2014; 7(11):4434-40. · 1.42 Impact Factor
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    ABSTRACT: Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since the IVA genome does not have the processing protease for the viral hemagglutinin (HA) envelope glycoprotein precursors, entry of this virus into cells and infectious organ tropism of IAV are primarily determined by host cellular trypsin-type HA processing proteases. Several secretion-type HA processing proteases for seasonal IAV in the airway, and ubiquitously expressed furin and pro-protein convertases for highly pathogenic avian influenza (HPAI) virus, have been reported. Recently, other HA-processing proteases for seasonal IAV and HPAI have been identified in the membrane fraction. These proteases proteolytically activate viral multiplication at the time of viral entry and budding. In addition to the role of host cellular proteases in IAV pathogenicity, IAV infection results in marked upregulation of cellular trypsins and matrix metalloproteinase-9 in various organs and cells, particularly endothelial cells, through induced pro-inflammatory cytokines. These host cellular factors interact with each other as the influenza virus-cytokine-protease cycle, which is the major mechanism that induces vascular hyperpermeability and multiorgan failure in severe influenza. This mini-review discusses the roles of cellular proteases in the pathogenesis of IAV and highlights the molecular mechanisms of upregulation of trypsins as effective targets for the control of IAV infection. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
    Biochimica et Biophysica Acta 07/2011; 1824(1):186-94. DOI:10.1016/j.bbapap.2011.07.001 · 4.66 Impact Factor
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    ABSTRACT: Interleukin-6 (IL-6) is a cytokine involved in different physiologic and pathophysiologic processes including essential hypertension (EH). Associations of the IL-6 promoter region polymorphisms with circulating level of IL-6 have been reported in various studies. We detected the IL-6-597G/A polymorphism in 246 EH patients and 194 healthy controls from Jiangsu area (south of China). Individuals all carried the GG wild genotype, no GA or AA genotypes were found. Our results suggest that IL-6-597G/A polymorphism is extremely rare and unlikely to be contributing significantly to disease susceptibility in southern Han Chinese.
    Cytokine 07/2011; 55(1):1-3. DOI:10.1016/j.cyto.2011.03.006 · 2.87 Impact Factor
  • Hai-Yan Pan, Mihiro Yano, Hiroshi Kido
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    ABSTRACT: Severe influenza sometimes causes myocarditis. We recently found that influenza A virus (IAV) infection induces various cellular factors, such as proinflammatory cytokines IL-6, IL-1β and TNF-α, matrix metalloproteinases (MMPs) and ectopic trypsin in mice hearts and in H9c2 cardiomyocytes. The induction of these cellular factors in turn promotes viral replication, myocardial inflammation and cellular damage through their intracellular signal transductions in cooperation with the IAV-induced Toll-like receptors (TLRs) and proteinase-activated receptor-2 (PAR-2) signalings, although the precise nature of these interactions remain obscure. By using specific inhibitors of TLRs and PAR-2 signalings and trypsin inhibitor aprotinin, we analyzed the role of TLR signaling and PAR-2 signaling in the IAV-induced pathological changes in cardiomyocytes. Inhibitors of TLR7/8-Myeloid Differentiation factor 88-nuclear factor-κB signaling and aprotinin effectively suppressed IAV-induced upregulation of proinflammatory cytokines, MMPs, trypsinogen and viral replication. Inhibitor of TLR3-Toll/interleukin-1 receptor domain-containing adaptor inducing interferons-dependent signaling predominantly suppressed the upregulation of interferon-β, a key intracellular host immune response factor. In contrast to the suppressive effect of trypsin inhibitor aprotinin on IAV replication, PAR-2 inhibitor FSY-NH(2), induced marginal upregulation of trypsinogen and subsequent stimulation of IAV replication.
    The Journal of Medical Investigation 02/2011; 58(1-2):19-28. DOI:10.2152/jmi.58.19
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    ABSTRACT: Influenza A virus (IAV) infection markedly up-regulates ectopic trypsins in various organs, viral envelope glycoprotein processing proteases, which are pre-requisites for virus entry and multiplication. We investigated the pathological roles of trypsin up-regulation in the progression of IAV-induced myocarditis, cytokine induction, and viral replication in the hearts, and also investigated the protective effects of trypsin inhibitor on cardiac dysfunction in vivo and selective knockdown of trypsin on IAV-induced cellular damage in cardiomyoblasts. The relationship of the expression among IAV RNA, trypsins, matrix metalloproteinase (MMP)-9, MMP-2, pro-inflammatory cytokines interleukin (IL)-6, IL-1β, and tumour necrosis factor-α was analysed in mice hearts and cardiomyoblasts after IAV infection. The severity of myocarditis was most noticeable during Day 6-9 post-infection, along with peak expression of viral RNA, trypsins, particularly trypsin₂, MMPs, and cytokines. Cardiac ATP levels were the lowest at Day 9. Up-regulated trypsins, viral protein, and tissue-injured loci in the myocardium were closely localized. Trypsin inhibitor aprotinin treatment in vivo and selective trypsin₁- and trypsin₂-knockdown, particularly the latter, in H9c2 cardiomyoblasts significantly suppressed viral replication, up-regulation of MMPs, and production of active MMP-9 and cytokines, resulting in marked protection against cellular damage, ATP depletion, and apoptosis. IAV infection-induced cardiac dysfunction monitored by echocardiography was improved significantly by aprotinin treatment. IAV-induced trypsins, particularly trypsin₂, in the myocardium trigger acute viral myocarditis through stimulation of IAV replication, proMMP-9 activation, and cytokine induction. These results suggest that up-regulation of trypsins is one of the key host pathological findings in IAV-induced myocarditis.
    Cardiovascular Research 11/2010; 89(3):595-603. DOI:10.1093/cvr/cvq358 · 5.81 Impact Factor
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    ABSTRACT: Influenza A virus (IAV) is one of the most common infectious pathogens in humans and causes considerable morbidity and mortality. The recent spread of highly-pathogenic avian IAV H5N1 viruses has reinforced the importance of pandemic preparedness. In the pathogenesis of IAV infection, cellular proteases play critical roles in the process of viral entry into cells that subsequently leads to tissue damage in the infected organs. Since there are no processing protease for the viral membrane fusion glycoprotein hemagglutinin precursor (HA(0)) in IAV, entry of the virus into cells is determined primarily by the host cellular HA(0) processing proteases that proteolytically activate membrane fusion activity. HA(0) of seasonal human IAV has the consensus cleavage site motif Q(E)-T/X-R and is selectively processed by at least seven different trypsin-type processing proteases identified to-date in animal model experiments using mouse-adapted IAV or gene expression system in MDCK cells. As is the case for the highly pathogenic avian influenza (HPAI) A virus, endoproteolytic processing of the HA(0) occurs through ubiquitous cellular processing proteases, which selectively recognize the multi-basic consensus cleavage site motifs, such as R-X-K/R-R, and K-X-K/R-R. The cleavage enzymes for the R-X-K/R-R motif, but not K-X-K/R-R motif, have been reported to be furin and pro-protein convertase (PC)5/6 in the trans-Golgi network. Here we report new members of type II transmembrane serine proteases of the cell membrane, mosaic serine protease large form (MSPL) and its splice variant TMPRSS13, which recognize and cleave both R-X-K/R-R and K-X-K/R-R motifs without calcium. Furthermore, IAV infection significantly up-regulates a latent ectopic pancreatic trypsin, one of the potent HA processing proteases, and pro-matrix metalloprotease-9, in various organs. These proteases may synergistically damage the blood-brain barrier in the brain and basement membrane of blood vessels in various organs, resulting in severe edema and multiple organ failure. In this review, we discuss these proteases as new drug target molecules for IAV treatment acting by inhibition of IAV multiplication and prevention of multiple organ failure, other than anti-viral agents, viral neuraminidase inhibitors.
    Journal of molecular and genetic medicine: an international journal of biomedical research 02/2008; 3(1):167-75.