Yen-Chang Lin

West Virginia University, Morgantown, WV, United States

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Publications (11)45.33 Total impact

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    ABSTRACT: Increasing evidence has demonstrated the potential risks of cardiac arrhythmias (such as prolonged QT interval) using tyrosine kinase inhibitors for cancer therapy. We report here that a widely used selective inhibitor of Src tyrosine kinases, PP2, can inhibit and prevent isoproterenol stimulation of cardiac pacemaker activity. In dissected rat sinus node PP2 inhibited and prevented isoproterenol stimulation of spontaneous beating rate. In isolated sinus node myocytes PP2 suppressed the hyperpolarization-activated "funny" current (If) by negatively shifting the activation curve and decelerating activation kinetics, associated with decreased cell surface expression and reduced tyrosine phosphorylation of hyperpolarization-activated, cyclic nucleotide-modulated channel 4 (HCN4) channel proteins. In human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed isoproterenol stimulation of HCN4 and inhibited HCN4-573x, a cAMP insensitive human HCN4 mutant. Isoprotenrenol had little effects on HCN4-573x. These results demonstrated that inhibition of presumably tyrosine Src kinase activity in heart by PP2 decreased and prevented the potential β-adrenergic stimulation of cardiac pacemaker activity. These effects are mediated, at least partially, by a cAMP-independent attenuation of channel activity and cell surface expression of HCN4, the key channel protein that controls the heart rate.
    Journal of cardiovascular pharmacology 02/2014; · 2.83 Impact Factor
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    ABSTRACT: Abstract The inhalation of nano-sized air pollutant particles is a recognized risk factor for cardiovascular disease; however, the link between occupational exposure to engineered nanoparticles and adverse cardiovascular events remains unclear. In the present study, we demonstrated that pulmonary exposure of rats to ultrafine titanium dioxide (UFTiO2) significantly increased heart rate and depressed diastolic function of the heart in response to isoproterenol. Moreover, pulmonary inhalation of UFTiO2 elevated mean and diastolic blood pressure in response to norepinephrine. Pretreatment of the rats ip with the transient receptor potential (TRP) channel blocker ruthenium red inhibited substance P synthesis in nodose ganglia and associated functional and biological changes in the cardiovascular system. In conclusion, the effects of pulmonary inhalation of UFTiO2 on cardiovascular function are most likely triggered by a lung-nodose ganglia-regulated pathway via the activation of TRP channels in the lung.
    Nanotoxicology 04/2013; · 7.84 Impact Factor
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    ABSTRACT: The majority of diabetic patients who are overweight or obese die of heart disease. We suspect that the obesity-induced insulin resistance may lead to abnormal cardiac electrophysiology. We tested this hypothesis by studying an obese insulin-resistant rat model, the obese Zucker rat (OZR). Compared with the age-matched control, lean Zucker rat (LZR), OZR of 16-17 wk old exhibited an increase in QTc interval, action potential duration, and cell capacitance. Furthermore, the L-type calcium current (I(CaL)) in OZR exhibited defective inactivation and lost the complete inactivation back to the closed state, leading to increased Ca(2+) influx. The current density of I(CaL) was reduced in OZR, whereas the threshold activation and the current-voltage relationship of I(CaL) were not significantly altered. L-type Ba(2+) current (I(BaL)) in OZR also exhibited defective inactivation, and steady-state inactivation was not significantly altered. However, the current-voltage relationship and activation threshold of I(BaL) in OZR exhibited a depolarized shift compared with LZR. The total and membrane protein expression levels of Cav1.2 [pore-forming subunit of L-type calcium channels (LTCC)], but not the insulin receptors, were decreased in OZR. The insulin receptor was found to be associated with the Cav1.2, which was weakened in OZR. The total protein expression of calmodulin was reduced, but that of Cavβ2 subunit was not altered in OZR. Together, these results suggested that the 16- to 17-wk-old OZR has 1) developed cardiac hypertrophy, 2) exhibited altered electrophysiology manifested by the prolonged QTc interval, 3) increased duration of action potential in isolated ventricular myocytes, 4) defective inactivation of I(CaL) and I(BaL), 5) weakened the association of LTCC with the insulin receptor, and 6) decreased protein expression of Cav1.2 and calmodulin. These results also provided mechanistic insights into a remodeled cardiac electrophysiology under the condition of insulin resistance, enhancing our understanding of long QT associated with obese type 2 diabetic patients.
    AJP Heart and Circulatory Physiology 12/2011; 302(4):H1013-22. · 4.01 Impact Factor
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    Han-Gang Yu, Yen-Chang Lin
    Modern Pacemakers - Present and Future, 02/2011; , ISBN: 978-953-307-214-2
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    ABSTRACT: Ca(2+) entry is delicately controlled by inactivation of L-type calcium channel (LTCC) composed of the pore-forming subunit alpha1C and the auxiliary subunits beta1 and alpha2delta. Calmodulin is the key protein that interacts with the COOH-terminal motifs of alpha1C, leading to the fine control of LTCC inactivation. In this study we show evidence that a hyperpolarization-activated cyclic nucleotide-gated channel, HCN2, can act as a nonchannel regulatory protein to narrow the L-type Ca(2+) channel current-voltage curve. In the absence of LTCC auxiliary subunits, HCN2 can induce alpha1C inactivation. Without alpha2delta, HCN2-induced fast inactivation of alpha1C requires calmodulin. With alpha2delta, the alpha1C/HCN2/alpha2delta channel inactivation does not require calmodulin. In contrast, beta1-subunit plays a relatively minor role in the interaction of alpha1C with HCN2. The NH(2) terminus of HCN2 and the IQ motif of alpha1C subunit are required for alpha1C/HCN2 channel interaction. Ca(2+) channel inactivation is significantly slowed in hippocampus neurons (HNs) overexpressing HCN2 mutant lacking NH(2) terminus and accelerated in HNs overexpressing the wild-type HCN2 compared with HN controls. Collectively, these results revealed a potentially novel protection mechanism for achieving the LTCC inactivation via interaction with HCN2.
    AJP Cell Physiology 02/2010; 298(5):C1029-37. · 3.71 Impact Factor
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    ABSTRACT: Therapeutic strategies such as using channel blockers and reducing culture temperature have been used to rescue some long QT-associated voltage-gated potassium Kv trafficking defective mutant channels. A hyperpolarization-activated cyclic nucleotide-gated HCN4 pacemaker channel mutant (D553N) has been recently found in a patient associated with cardiac arrhythmias including long QT. D553N showed the defective trafficking to the cell surface, leading to little ionic current expression (loss-of-function). We show in this report that enhanced tyrosine phosphorylation mediated by Src, Fyn, and Yes kinases was able to restore the surface expression of D553N for normal current expression. Src or Yes, but not Fyn, significantly increased the current density and surface expression of D553N. Fyn accelerated the activation kinetics of the rescued D553N. Co-expression of D553N with Yes exhibited the slowest activation kinetics of D553N. Src, Fyn, and Yes significantly enhanced the tyrosine phosphorylation of D553N. A combination of Src, Fyn, and Yes rescued the current expression and the gating of D553N comparable with those of wild-type HCN4. In conclusion, we demonstrate a novel mechanism using three endogenous Src kinases to rescue a trafficking defective HCN4 mutant channel (D553N) by enhancing the tyrosine phosphorylation of the mutant channel protein.
    Journal of Biological Chemistry 10/2009; 284(44):30433-30440. · 4.65 Impact Factor
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    ABSTRACT: Therapeutic strategies such as using channel blockers and reducing culture temperature have been used to rescue some long QT-associated voltage-gated potassium Kv trafficking defective mutant channels. A hyperpolarization-activated cyclic nucleotide-gated HCN4 pacemaker channel mutant (D553N) has been recently found in a patient associated with cardiac arrhythmias including long QT. D553N showed the defective trafficking to the cell surface, leading to little ionic current expression (loss-of-function). We show in this report that enhanced tyrosine phosphorylation mediated by Src, Fyn, and Yes kinases was able to restore the surface expression of D553N for normal current expression. Src or Yes, but not Fyn, significantly increased the current density and surface expression of D553N. Fyn accelerated the activation kinetics of the rescued D553N. Co-expression of D553N with Yes exhibited the slowest activation kinetics of D553N. Src, Fyn, and Yes significantly enhanced the tyrosine phosphorylation of D553N. A combination of Src, Fyn, and Yes rescued the current expression and the gating of D553N comparable with those of wild-type HCN4. In conclusion, we demonstrate a novel mechanism using three endogenous Src kinases to rescue a trafficking defective HCN4 mutant channel (D553N) by enhancing the tyrosine phosphorylation of the mutant channel protein.
    Journal of Biological Chemistry 09/2009; 284(44):30433-40. · 4.65 Impact Factor
  • Han-Gang Yu, Jianying Huang, Yen-Chang Lin
    Journal of Biological Chemistry 09/2009; 284(39):le7; author reply le8. · 4.65 Impact Factor
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    Qi Zhang, Aijie Huang, Yen-Chang Lin, Han-Gang Yu
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    ABSTRACT: The time- and voltage-dependent inward current generated by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contributes to the tissue-specific rhythmic activities in the brain and heart. Four isoforms (HCN1-HCN4) have been identified. Previous studies showed that different HCN isoforms may form functional heteromeric channels. We report here that when HCN2 and HCN4 mRNA were injected into Xenopus oocytes with various ratios of HCN2 over HCN4 at 1:1, 10:1, and 1:10, respectively, the resultant channels showed a depolarized current activation and significantly faster activation kinetics near the midpoint of activation compared with HCN4 homomeric channels. In adult rat myocytes overexpressing HCN4, there was an associated increase in HCN2 mRNA. In neonatal rat myocytes in which HCN2 was knocked down, there was also a simultaneous decrease in HCN4 mRNA. Coimmunoprecipitation experiments showed that HCN2 and HCN4 channel proteins can associate with each other in adult rat ventricles. Finally, in adult myocytes overexpressing HCN4, the hyperpolarization-activated inward current activation, I(f), was shifted to physiological voltages from non-physiological voltages, associated with faster activation kinetics. These data suggested that different ratios of HCN2 and HCN4 transcripts overlapping in different tissues also contribute to the tissue-specific properties of I(f).
    Biochimica et Biophysica Acta 03/2009; 1788(5):1138-47. · 4.66 Impact Factor
  • Biophysical Journal 01/2009; 96(3). · 3.67 Impact Factor
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    ABSTRACT: We have previously reported an important role of increased tyrosine phosphorylation activity by Src in the modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Here we provide evidence showing a novel mechanism of decreased tyrosine phosphorylation on HCN channel properties. We found that the receptor-like protein-tyrosine phosphatase-alpha (RPTPalpha) significantly inhibited or eliminated HCN2 channel expression in HEK293 cells. Biochemical evidence showed that the surface expression of HCN2 was remarkably reduced by RPTPalpha, which was in parallel to the decreased tyrosine phosphorylation of the channel protein. Confocal imaging confirmed that the membrane surface distribution of the HCN2 channel was inhibited by RPTPalpha. Moreover, we detected the presence of RPTPalpha proteins in cardiac ventricles with expression levels changed during development. Inhibition of tyrosine phosphatase activity by phenylarsine oxide or sodium orthovanadate shifted ventricular hyperpolarization-activated current (I(f), generated by HCN channels) activation from nonphysiological voltages into physiological voltages associated with accelerated activation kinetics. In conclusion, we showed a critical role RPTPalpha plays in HCN channel function via tyrosine dephosphorylation. These findings are also important to neurons where HCN and RPTPalpha are richly expressed.
    Journal of Biological Chemistry 10/2008; 283(44):29912-9. · 4.65 Impact Factor