研究等業績 - 原著論文 - 渡邊 博之
-
TRPV1 and TRPA1 in pulmonary vagal afferents and their relations to airway sensitivity
Hiroyuki Watanabe, Takayoshi Ohba, Kazuhiro Satoh, Masaaki Sano, Takanobu Shioya and Hiroshi Ito
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 10 ( 1 ) 18 - 30 2011年02月 [査読有り]
研究論文（学術雑誌）
In the last 15 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge about the molecular basis of sensory function in pulmonary vagal afferents. In particular, TRPV1 and TRPA1 channels are unique cellular sensors for a wide range of inflammatory mediators and noxious irritants. These channels act as the molecular integrator of multiple nociceptive stimuli and are involved in multiple cellular functions, ranging from transduction of sensory signals to the release of neuropeptides in pulmonary vagal afferents. Increased activity of TRPV1 channels is now recognized as a cause of airway hypersensitivity in inflammatory airway diseases. In this review, we summarize current knowledge about the activation mechanisms of TRPV1 and TRPA1, and discuss the possible functional implications of TRPV1 and TRPA1 in human physiology and pathophysiology, such as the cough reflex and hypersensitivity.
-
Cardiac Diagnosing by a Piezoelectric-transducer-based Heart Sound Monitor System
Shinichi Sato, Takashi Koyama, Kyoichi Ono, Gen Igarashi, Hiroyuki Watanabe, Hiroshi Ito, Mikio Muraoka
BIODEVICES 280 - 283 2011年01月 [査読有り]
研究論文（学術雑誌）
-
Fluvastatin protects vascular smooth muscle cells against oxidative stress through the Nrf2-dependent antioxidant pathway.
Shin Makabe, Yoichiro Takahashi, Hiroyuki Watanabe, Manabu Murakami, Takayoshi Ohba, Hiroshi Ito
Atherosclerosis 213 ( 2 ) 377 - 84 2010年12月 [査読有り]
研究論文（学術雑誌）
OBJECTIVE: HMG-CoA reductase inhibitors (statins) have pleiotropic actions, including the ability to reduce vascular oxidative stress. Transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular oxidative stress. This study examined the role of Nrf2 in statin-mediated antioxidant effects in vascular smooth muscle cells. METHODS AND RESULTS: In cultured human coronary artery smooth muscle cells (hCASMCs), fluvastatin activated the nuclear translocation of Nrf2, as evaluated by Western blotting and immunocytochemical analyses. Nrf2-antioxidant response element (ARE) activity was measured with a luciferase assay after transfection of reporter plasmids containing AREs. Fluvastatin significantly increased the transcriptional activity of the ARE. Electromobility shift assays using an ARE probe detected a complex that was significantly increased in intensity by fluvastatin. Western blotting and luciferase assay revealed fluvastatin activated Nrf2 via the PI3K/Akt pathway. Statins upregulated the Nrf2-related antioxidant genes heme oxygenase-1, NAD(P)H quinone oxidoreductase-1, and glutamate-cysteine ligase modifier subunits. Inhibition of Nrf2 by siRNA reduced statin-induced upregulation of these antioxidant genes. Moreover, Nrf2 siRNA markedly reduced the cytoprotective effects of fluvastatin against H(2)O(2) administration in hCASMCs. CONCLUSIONS: Fluvastatin exerts cytoprotective effects against oxidative stress, inducing antioxidant genes through Nrf2/ARE in hCASMCs. These results suggest that the Nrf2/ARE pathway plays an important role in the regulation of statin-mediated antioxidant effects in vascular smooth muscle cells.
-
Beneficial effects of adaptive servo ventilation in patients with chronic heart failure.
Takashi Koyama, Hiroyuki Watanabe, Yusuke Kobukai, Shin Makabe, Yoshiko Munehisa, Kenji Iino, Toshimitsu Kosaka, Hiroshi Ito
Circulation journal : official journal of the Japanese Circulation Society 74 ( 10 ) 2118 - 24 2010年10月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Sleep-disordered breathing (SDB) is thought to be a state of inflammation caused by hypoxic stress. Whether adaptive servo ventilation (ASV) attenuates the inflammatory response and improves the cardiac function of patients with congestive heart failure (CHF) accompanied by SDB was not been investigated. METHODS AND RESULTS: Seventeen inpatients with New York Heart Association (NYHA) II or III underwent polysomnography. There was a positive correlation between the apnea hypopnea index and high-sensitivity C-reactive protein (hs-CRP) level (r=0.753, P=0.016). The patients were divided into ASV (n=10) and non-ASV groups (n=7), and CHF-parameters were measured before and after ASV treatment. Improvement was noted for the NYHA class in the ASV group but not in the non-ASV group. In contrast to the non-ASV group, the level of brain natriuretic peptide (BNP), ejection fraction, and hs-CRP levels in the ASV group significantly improved (BNP, 212.1 ± 181.2 to 77.3 ± 54.0 pg/ml [P<0.05]; ejection fraction, 43.5 ± 6.4 to 53.3 ± 6.1% [P=0.002]; hs-CRP, 0.85 ± 0.58 to 0.21 ± 0.19 mg/dl, [P=0.008]). The increase in ejection fraction was correlated with a decrease in the hs-CRP level (r=-0.753, P=0.001). CONCLUSIONS: Anti-inflammatory effects of ASV are important contributors for improving cardiac function in patients with CHF accompanied by SDB.
-
Decreased calcium channel currents and facilitated epinephrine release in the Ca2+ channel beta3 subunit-null mice.
Toshio Ohta, Takayoshi Ohba, Takashi Suzuki, Hiroyuki Watanabe, Hironobu Sasano, Manabu Murakami
Biochemical and biophysical research communications 394 ( 3 ) 464 - 9 2010年04月 [査読有り]
研究論文（学術雑誌）
The beta subunits of voltage-dependent calcium channels are known to modify calcium channel currents through pore-forming alpha1 subunits. The beta3 subunit is expressed in the adrenal gland and participates in forming various calcium channel types. We performed a series of experiments in beta3-null mice to determine the role of the beta3 subunit in catecholamine release from the adrenal chromaffin system. Protein levels of N-type channel forming CaV2.2 and L-type forming CaV1.2 decreased. The beta3-null mice showed a decreased baroreflex, suggesting decreased sympathetic tonus, whereas plasma catecholamine levels did not change. Pulse-voltage stimulation revealed significantly increased amperometrical currents in beta3-null mice, while patch-clamp recordings showed a significant reduction in Ca(2+)-currents due to reduced L- and N-type currents, indicating facilitated exocytosis. A biochemical analysis revealed increased InsP3 production. In conclusion, our results indicate the importance of the beta3 subunit in determining calcium channel characteristics and catecholamine release in adrenal chromaffin cells.
-
Double transgenic mice crossed GFP-LC3 transgenic mice with alphaMyHC-mCherry-LC3 transgenic mice are a new and useful tool to examine the role of autophagy in the heart.
Mai Terada, Kiyoshi Nobori, Yoshiko Munehisa, Manabu Kakizaki, Takayoshi Ohba, Yoichiro Takahashi, Takashi Koyama, Yutaka Terata, Masaru Ishida, Kenji Iino, Toshimitsu Kosaka, Hiroyuki Watanabe, Hitoshi Hasegawa, Hiroshi Ito
Circulation journal : official journal of the Japanese Circulation Society 74 ( 1 ) 203 - 6 2010年01月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: The involvement of autophagy in heart disease has been reported. Transgenic mice expressing GFP-LC3 have been a useful tool in detecting autophagosomes systemically. It is difficult to differentiate increased formation of autophagosomes from decreased clearance of autophagosomes in the heart using GFP-LC3 mice. METHODS AND RESULTS: We generated transgenic mice expressing mCherry-LC3 under alphaMyHC promoter and crossed the mice with transgenic mice expressing GFP-LC3. The deference of resistance to acidic conditions between GFP and mCherry overcame the limitation. CONCLUSIONS: This method is an innovative approach to examine the role of autophagy and to analyze autophagosome maturation in cardiomyocytes. (Circ J 2010; 74: 203 - 206).
-
Essential role of STIM1 in the development of cardiomyocyte hypertrophy.
Takayoshi Ohba, Hiroyuki Watanabe, Manabu Murakami, Takako Sato, Kyoichi Ono, Hiroshi Ito
Biochemical and biophysical research communications 389 ( 1 ) 172 - 6 2009年11月 [査読有り]
研究論文（学術雑誌）
Store-operated Ca(2+) entry (SOCE) through transient receptor potential (TRP) channels is important in the development of cardiac hypertrophy. Recently, stromal interaction molecule 1 (STIM1) was identified as a key regulator of SOCE. In this study, we examined whether STIM1 is involved in the development of cardiomyocyte hypertrophy. RT-PCR showed that cultured rat cardiomyocytes constitutively expressed STIM1. Endothelin-1 (ET-1) treatment for 48h enhanced TRPC1 expression, SOCE, and nuclear factor of activated T cells activation without upregulating STIM1. However, the knockdown of STIM1 suppressed these effects, thereby preventing a hypertrophic response. These results suggest that STIM1 plays an essential role in the development of cardiomyocyte hypertrophy.
-
Direct effect of percutaneous transluminal angioplasty on the heart in patient with peripheral artery disease
Oguma Yasunori,Iino Kenji,Watanabe Hiroyuki,Kosaka Toshimitsu,Hasegawa Hitoshi,Ito Hiroshi
秋田医学 36 ( 2 ) 107 - 113 2009年11月 [査読有り]
研究論文（学術雑誌）
Background and Purpose : The patient with peripheral artery disease (PAD) is known to have a poor prognosis for life. Recently, it has been reported that percutaneous transluminal angioplasty (PTA) for PAD improves the prognosis. However, the detailed mechanisms remain unclear.
Augmentation index (AIx) or central aortic pressure (CAP) is shown to increase myocardial mechanical stress and facilitate myocardial hypertrophy. The aim of this study is to clarify the direct cardioprotective effects of PTA mediated by decreasing CAP and AIx.
Methods : 28 patients with PAD were enrolled. They were divided into two groups ; control group (n=12) and PTA group (n=16). Both radial AIx and CAP were measured by using pulse waveform analysis of arterial waveform recorded non-invasively by applanation tonometry in radial artery. We used a plasma B-type natriuretic peptide (BNP) level as a marker of myocardial mechanical stress. Plasma BNP levels, radial AIx and CAP which were measured after PTA or angiography, were compared with the data on admission.
Result : Although plasma BNP levels in the control group were not changed, those in the PTA group were significantly decreased from 68.44 to 42.08 pg/ml (p<0.05). Pulse waveform analysis demonstrated that radial AIx and CAP in the control group remain unchanged. On the other hand, radial AIx and CAP were significantly reduced in the PTA group. The reduction rates of radial AIx, CAP and plasma BNP levels were −11.3%, −8.9% and −34% respectively.
Conclusion : These results suggest that PTA can decrease myocardial mechanical stress in patients with PAD. The mechanisms may be mediated in part by reduction of radial AIx and CAP. -
Cardioprotective effect of an L/N-type calcium channel blocker in patients with hypertensive heart disease.
Toshimitsu Kosaka, Masayasu Nakagawa, Masaru Ishida, Kenji Iino, Hiroyuki Watanabe, Hitoshi Hasegawa, Hiroshi Ito
Journal of cardiology 54 ( 2 ) 262 - 72 2009年10月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Left ventricular (LV) diastolic dysfunction is related to increased cardiac sympathetic activity. We investigated the effect of cilnidipine, an L/N-type calcium channel blocker, on LV diastolic function and cardiac sympathetic activity in patients with hypertensive heart disease (HHD) using radionuclide myocardial imaging. METHODS AND RESULTS: Thirty-two frame electrocardiography (ECG) -gated (99m)Tc-sestamibi (MIBI) myocardial single photon emission computed tomography (SPECT), and (123)I-metaiodobenzylguanidine (MIBG) imaging were performed before and 6 months after drug administration in 32 outpatients with HHD. Sixteen of the patients were treated with cilnidipine and the other 16 were treated with nifedipine retard. The parameters for assessing LV diastolic function evaluated using ECG-gated (99m)Tc-MIBI SPECT were peak filling rate (PFR), first-third filling rate (1/3FR), and time to peak filling (TPF). Cardiac sympathetic activity was assessed as early and delayed heart to mediastinum (H/M) ratios and a washout rate (WR), using (123)I-MIBG imaging. The PFR and 1/3FR significantly increased after 6 months of treatment with cilnidipine (p<0.05 for both), but did not with nifedipine retard. The H/M ratios significantly increased (p<0.05 for both) in conjunction with a decreased WR (p<0.05) in the cilnidipine group. Moreover, a significant positive correlation was seen between the rate of change in PFR and the rate of change in early and delayed H/M ratios in the cilnidipine group (p<0.05 for both). The same results were obtained for the relationship between the rate of change in 1/3FR and the rate of change in H/M ratios (p<0.05 for both). However, no such relationship was seen in the nifedipine group. CONCLUSION: These data indicate that cilnidipine seems to suppress cardiac sympathetic overactivity via blockade of N-type calcium channels and improves LV diastolic function in patients with HHD.
-
Association between perceived stress and plasma B-type natriuretic peptide concentrations.
Megumi Koizumi, Yoshihiro Kaneko, Shinya Tosa, Hiroyuki Watanabe, Toshimitsu Kosaka, Hitoshi Hasegawa, Yutaka Motohashi, Hiroshi Ito
Circulation journal : official journal of the Japanese Circulation Society 73 ( 6 ) 1055 - 61 2009年06月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Many patients with heart disease continue to have cardiac events despite receiving optimal treatments for traditional risk factors. Consequently, non-traditional risk factors for heart disease, such as perceived stress, have attracted attention. Associations between perceived stress and plasma B-type natriuretic peptide (BNP) were explored, while controlling for traditional heart disease risk factors. METHODS AND RESULTS: This cross-sectional study examined 360 male and 446 female (age, >40 years) residents of a rural Japanese community who received annual health checkups in 2006. A lifestyle questionnaire was used to obtain information regarding perceived stress and medical history, and routine anthropometric and blood pressure measurements and a laboratory assessment of cardiovascular risk factors, including plasma BNP concentrations and an electrocardiogram, were done. After adjusting for traditional heart disease risk factors, multiple regression analysis showed that perceived stress was associated with BNP concentrations, particularly in women (F=6.12, P=0.026). In addition, multiple tests using Bonferroni's procedure showed that BNP concentrations decreased with perceived stress level in men and women. Similar trends were observed in the sub-analyses of subjects with and without known heart disease. CONCLUSIONS: Perceived stress in our study was negatively associated with plasma BNP concentrations, independently of traditional heart disease risk factors.
-
Renal transplantation improves cardiac function
MUNEHISA Yoshiko,WATANABE Hiroyuki,TERATA Shigenori,KOSAKA Toshimitsu,HASEGAWA Hitoshi,SATOH Shigeru,HABUCHI Tomonori,ITO Hiroshi
秋田医学 36 ( 1 ) 59 - 66 2009年06月 [査読有り]
研究論文（学術雑誌）
There is mounting evidence that chronic kidney disease is a major contributor to severe cardiac damage. Although renal transplantation (RT) is an effective strategy in patients with end-stage renal disease (ESRD), the effects on cardiac function remain unclear. This study determined the effects of RT on left ventricular (LV) morphology and function in a retrospective longitudinal analysis of echocardiographic data collected in RT (n=17) and maintenance hemodialysis (HD ; n=19) groups from 2003 to 2008.
Echocardiographic data obtained within 6 months and at over 3 years were compared with the data before transplantation. Improved blood pressure and anemia were observed with RT, but not HD. In contrast to the HD group, the left ventricular mass index (LVMI) in the RT group was decreased from 195.2 ± 52.1 to 162.5 ± 30.8 g/m2 ( p<0.05). In addition, the LV ejection fraction was improved in the RT group from 63.0 ± 17.1% to 79.5 ± 3.3% ( p<0.01), but not in the HD group. The rate of reduction of LVMI in the RT group was greater in patients with good control of hemoglobin.
In conclusion, RT has beneficial effects on LV hypertrophy and function, as well as on ESRD. -
The pathological role of transient receptor potential channels in heart disease.
Hiroyuki Watanabe, Manabu Murakami, Takayoshi Ohba, Kyoichi Ono, Hiroshi Ito
Circulation journal : official journal of the Japanese Circulation Society 73 ( 3 ) 419 - 27 2009年03月 [査読有り]
研究論文（学術雑誌）
Transient receptor potential (TRP) channels are expressed in almost every human tissue, including the heart and vasculature. Most are permeable to Ca(2+) and play unique roles as multifunctional cellular sensors. Their involvement in many fundamental cell functions (eg, contraction, proliferation, and cell death) has made investigating their roles in human disease an urgent priority for medical science. This review presents an overview of current knowledge about the pathological role of TRP channels in heart disease and highlights some TRP channels with anticipated roles in disease. Evidence suggests that (a) upregulation of TRPC channels is involved in the development of cardiac hypertrophy and heart failure; (b) TRPC1, TRPC6, and TRPV2 play a role in the pathogenesis of cardiomyopathy associated with muscular dystrophy; (c) TRPC6 or TRPM4 is involved in the delayed after-depolarization; (d) TRPP2 is involved in the normal development of the interventricular and interatrial septa; and (e) neuronal TRPV1 acts as a detector of pain-producing stimuli. Ultimately, TRP channels might become novel pharmacological targets in the treatment of human heart disease.
-
Usefulness of plasma BNP levels as a marker of left ventricular wall stress in obese individuals.
Shinya Tosa, Hiroyuki Watanabe, Kenji Iino, Gen Terui, Toshimitsu Kosaka, Hitoshi Hasegawa, Hiroshi Ito
International heart journal 50 ( 2 ) 173 - 82 2009年03月 [査読有り]
研究論文（学術雑誌）
Plasma brain natriuretic peptide (BNP) level is known to reflect left ventricular wall stress (LVWS). Recent studies have shown that obese individuals have lower BNP levels. However, the usefulness of BNP level as a marker of LVWS in obese individuals remains unclear. This study examined whether BNP reflects LVWS even in obese individuals.This study enrolled 136 hospital inpatients who had suffered chronic heart failure (NYHA class I or II), or who had undergone a thorough examination for angina pectoris. On the basis of body mass index (BMI), we divided the inpatients into nonobese (< 25) and obese (> or = 25) groups. All BNP measurements, cardiac catheterizations, and echocardiographic examinations were carried out within 24 hours. Although no significant differences were found between the two groups in the hemodynamic parameters examined, including end-diastolic LVWS (LV-EDWS) and end-systolic LVWS (LV-ESWS), BNP levels were significantly lower in the obese group compared to the nonobese group. In the nonobese group, a definite correlation between LV-EDWS or LV-ESWS and BNP (r = 0.43, r = 0.46, respectively) was observed, whereas no correlation was found between LV-EDWS or LV-ESWS and BNP in the obese group (r = -0.09, r = 0.06, respectively). To explore the mechanism for suppressed BNP levels in obese individuals, the correlation of BNP with biochemical markers was analyzed. Statistical significance was found only between adiponectin and BNP (r = 0.44), implying that BNP or adiponectin might influence the plasma levels of the other.In conclusion, BNP levels cannot be used as a marker of LVWS in obese individuals.
-
Molecular and electrical remodeling of L- and T-type Ca(2+) channels in rat right atrium with monocrotaline-induced pulmonary hypertension.
Takashi Koyama, Kyoichi Ono, Hiroyuki Watanabe, Takayoshi Ohba, Manabu Murakami, Kenji Iino, Hiroshi Ito
Circulation journal : official journal of the Japanese Circulation Society 73 ( 2 ) 256 - 63 2009年02月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Atrial arrhythmia is often encountered in chronic pulmonary disease with pulmonary hypertension (PH), but few studies have investigated the electrical remodeling of atrial Ca(2+) channels under PH. METHODS AND RESULTS: Wistar rats were injected with monocrotaline (MCT), resulting in PH with right atrial and ventricular hypertrophy. The L-type Ca(2+) channel current density was significantly decreased in right atrial cells of MCT-treated rats, accompanied by a significant reduction in mRNA expression of the CaV1.2 (alpha(1C)) subunit and accessory beta(2) subunit. Conversely, the low voltage-activated Ca(2+) current was more marked in the right atrial cells of MCT-treated rats than in those of control rats. The current-voltage relationship and the time course of inactivation closely resembled those of T-type Ca(2+) channels, although the current was only slightly inhibited by 10-100 micromol/L Ni(2+). No significant differences were observed in the mRNA expression levels of CaV3.1 (alpha(1G)) and CaV3.2 (alpha(1H)) or the protein level of the CaV3.1 subunit. In left atrial cells, the electrophysiological molecular properties of Ca(2+) channels were unaffected by MCT treatment. CONCLUSIONS: PH causes right atrial hypertrophy, associated with alteration of the electrophysiological molecular properties of Ca(2+) channels.
-
Modified sympathetic nerve system activity with overexpression of the voltage-dependent calcium channel beta3 subunit.
Manabu Murakami, Takayoshi Ohba, Feng Xu, Eisaku Satoh, Ichiro Miyoshi, Takashi Suzuki, Yoichirou Takahashi, Eiki Takahashi, Hiroyuki Watanabe, Kyoichi Ono, Hironobu Sasano, Noriyuki Kasai, Hiroshi Ito, Toshihiko Iijima
The Journal of biological chemistry 283 ( 36 ) 24554 - 60 2008年09月 [査読有り]
研究論文（学術雑誌）
N-type voltage-dependent calcium channels (VDCCs) play determining roles in calcium entry at sympathetic nerve terminals and trigger the release of the neurotransmitter norepinephrine. The accessory beta3 subunit of these channels preferentially forms N-type channels with a pore-forming CaV2.2 subunit. To examine its role in sympathetic nerve regulation, we established a beta3-overexpressing transgenic (beta3-Tg) mouse line. In these mice, we analyzed cardiovascular functions such as electrocardiography, blood pressure, echocardiography, and isovolumic contraction of the left ventricle with a Langendorff apparatus. Furthermore, we compared the cardiac function with that of beta3-null and CaV2.2 (alpha1B)-null mice. The beta3-Tg mice showed increased expression of the beta3 subunit, resulting in increased amounts of CaV2.2 in supracervical ganglion (SCG) neurons. The beta3-Tg mice had increased heart rate and enhanced sensitivity to N-type channel-specific blockers in electrocardiography, blood pressure, and echocardiography. In contrast, cardiac atria of the beta3-Tg mice revealed normal contractility to isoproterenol. Furthermore, their cardiac myocytes showed normal calcium channel currents, indicating unchanged calcium influx through VDCCs. Langendorff heart perfusion analysis revealed enhanced sensitivity to electric field stimulation in the beta3-Tg mice, whereas beta3-null and Cav2.2-null showed decreased responsiveness. The plasma epinephrine and norepinephrine levels in the beta3-Tg mice were significantly increased in the basal state, indicating enhanced sympathetic tone. Electrophysiological analysis in SCG neurons of beta3-Tg mice revealed increased calcium channel currents, especially N- and L-type currents. These results identify a determining role for the beta3 subunit in the N-type channel population in SCG and a major role in sympathetic nerve regulation.
-
TRP channel and cardiovascular disease.
Hiroyuki Watanabe, Manabu Murakami, Takayoshi Ohba, Yoichiro Takahashi, Hiroshi Ito
Pharmacology & therapeutics 118 ( 3 ) 337 - 51 2008年06月 [査読有り]
研究論文（学術雑誌）
The transient receptor potential (TRP) channel superfamily consists of 28 mammalian cation channels and is expressed in almost every tissue, including the heart and vasculature; most TRP channels are permeable to Ca(2+) and are prime molecular candidates for store-operated channels (SOCs), receptor-operated channels (ROCs), ligand-gated channels (LGCs) and stretch-activated channels (SACs). As these channels act as multifunctional cellular sensors and are involved in several fundamental cell functions such as contraction, proliferation and cell death, investigation of their roles in human disease is very important. This review presents an overview of current knowledge about the pathological role of TRP channels in cardiovascular diseases and highlights some TRP channels for which a role in the diseases can be anticipated. Evidences suggest that up-regulation of TRPC channels is involved in the development of cardiac hypertrophy and heart failure; TRPM4 participates in some features of cardiac arrhythmias; increased expression of TRPC channels is associated with vascular remodeling and pulmonary hypertension; reduced expression or activity of TRPV4 impairs endothelium-dependent vasorelaxation; TRPC3/C4 and TRPM2 act as endothelial redox sensors; and TRPC1, -C4, -C6, -V4, and -M2, have been implicated in endothelial barrier dysfunction. Ultimately, TRP channels will become important novel pharmacological targets for the treatment of human cardiovascular diseases.
-
Amlodipine inhibits cell proliferation via PKD1-related pathway.
Takayoshi Ohba, Hiroyuki Watanabe, Manabu Murakami, Milena Radovanovic, Kenji Iino, Masaru Ishida, Shinya Tosa, Kyoichi Ono, Hiroshi Ito
Biochemical and biophysical research communications 369 ( 2 ) 376 - 81 2008年05月 [査読有り]
研究論文（学術雑誌）
Human coronary artery smooth muscle cell (hCASMC) proliferation is involved in the progression of coronary artery disease. Amlodipine, a widely used antihypertensive drug, exerts antiproliferative effects by increasing the expression of p21((Waf1/Cip1)). Polycystic kidney disease 1 (PKD1) is also involved in cell cycle inhibition via p21((Waf1/Cip1)) up-regulation. We clarified the involvement of PKD1-related signaling on hCASMCs. Cultured hCASMCs, which constitutively express PKD1, were stimulated with 5% serum. Amlodipine increased p21((Waf1/Cip1)) expression in a dose- and time-dependent manner, resulting in reduced hCASMC proliferation. The inhibitory effect of amlodipine was mimicked by overexpression of PKD1 and was reversed by a dominant-negative version of PKD1 (R4227X). Immunoblot analysis showed that phosphorylated JAK2 was increased by amlodipine treatment or PKD1 overexpression. A luciferase assay revealed that the overexpression of PKD1 induced STAT1 enhancer activity. These data suggest that PKD1 contributes to the antiproliferative effect of amlodipine on hCASMCs via JAK/STAT signaling and p21((Waf1/Cip1)) up-regulation.
-
Functional role of stromal interaction molecule 1 (STIM1) in vascular smooth muscle cells.
Yoichiro Takahashi, Hiroyuki Watanabe, Manabu Murakami, Kyoichi Ono, Yoshiko Munehisa, Takashi Koyama, Kiyoshi Nobori, Toshihiko Iijima, Hiroshi Ito
Biochemical and biophysical research communications 361 ( 4 ) 934 - 40 2007年10月 [査読有り]
研究論文（学術雑誌）
We investigated the functional role of STIM1, a Ca(2+) sensor in the endoplasmic reticulum (ER) that regulates store-operated Ca(2+) entry (SOCE), in vascular smooth muscle cells (VSMCs). STIM1 was mainly localized at the ER and plasma membrane. The knockdown of STIM1 expression by small interfering (si) RNA drastically decreased SOCE. In contrast, an EF-hand mutant of STIM1, STIM1(E87A), produced a marked increase in SOCE, which was abolished by co-transfection with siRNA to transient receptor potential canonical 1 (TRPC1). In addition, transfection with siRNA against STIM1 suppressed phosphorylation of cAMP-responsive element binding protein (CREB) and cell growth. These results suggest that STIM1 is an essential component of SOCE and that it is involved in VSMC proliferation.