Masae Suetsugu
Yamaguchi University
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Featured researches published by Masae Suetsugu.
Circulation | 2003
Masafumi Yano; Shigeki Kobayashi; Masateru Kohno; Masahiro Doi; Takahiro Tokuhisa; Shinichi Okuda; Masae Suetsugu; Takayuki Hisaoka; Masakazu Obayashi; Tomoko Ohkusa; Michihiro Kohno; Masunori Matsuzaki
Background—The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload–induced myocardial injury. Methods and Results—Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. Conclusions—During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.
Circulation | 2000
Masafumi Yano; Kaoru Ono; Tomoko Ohkusa; Masae Suetsugu; Masateru Kohno; Takayuki Hisaoka; Shigeki Kobayashi; Yuji Hisamatsu; Takeshi Yamamoto; Michihiro Kohno; Naoya Noguchi; Shin Takasawa; Hiroshi Okamoto; Masunori Matsuzaki
BackgroundIn the pathogenesis of cardiac dysfunction in heart failure, a decrease in the activity of the sarcoplasmic reticulum (SR) Ca2+-ATPase is believed to be a major determinant. Here, we report a novel mechanism of cardiac dysfunction revealed by assessing the functional interaction of FK506–binding protein (FKBP12.6) with the cardiac ryanodine receptor (RyR) in a canine model of pacing-induced heart failure. Methods and ResultsSR vesicles were isolated from left ventricular muscles (normal and heart failure). The stoichiometry of FKBP12.6 per RyR was significantly decreased in failing SR, as assessed by the ratio of the Bmax values for [3H]dihydro-FK506 to those for [3H]ryanodine binding. In normal SR, the molar ratio was 3.6 (≈1 FKBP12.6 for each RyR monomer), whereas it was 1.6 in failing SR. In normal SR, FK506 caused a dose-dependent Ca2+ leak that showed a close parallelism with the conformational change in RyR. In failing SR, a prominent Ca2+ leak was observed even in the absence of FK506, and FK506 produced little or no further increase in Ca2+ leak and only a slight conformational change in RyR. The level of protein expression of FKBP12.6 was indeed found to be significantly decreased in failing SR. ConclusionsAn abnormal Ca2+ leak through the RyR is present in heart failure, and this leak is presumably caused by a partial loss of RyR-bound FKBP12.6 and the resultant conformational change in RyR. This abnormal Ca2+ leak might possibly cause Ca2+ overload and consequent diastolic dysfunction, as well as systolic dysfunction.
Cardiovascular Research | 2001
Takayuki Hisaoka; Masafumi Yano; Tomoko Ohkusa; Masae Suetsugu; Kaoru Ono; Masateru Kohno; Jyutaro Yamada; Shigeki Kobayashi; Michihiro Kohno; Masunori Matsuzaki
OBJECTIVE The Rho/Rho-kinase system regulates Ca(2+) sensitivity in vascular smooth muscle. A new drug, Y-27632, specifically inhibits Rho-kinase and hence decreases the phosphorylation of myosin light chain, thus reducing contraction. Here, we compare the effects of Y-27632 and nifedipine on the vasoconstrictor response of the femoral artery in heart failure. METHODS Heart failure (HF) was produced by chronic rapid RV pacing (250 bpm, 28 days, six dogs). Indo1-AM was loaded into endothelium-denuded femoral artery segments for measuring intracellular [Ca(2+)]. Tension and changes in intracellular [Ca(2+)] [the change in the ratio (418 nm/468 nm) of Indo1 fluorescence (F(ratio))] were simultaneously measured in Krebs-Ringer solution. RESULTS In HF: (i) norepinephrine (10 microM) produced greater tension (784+/-52 g/cm(2)) than in control (502+/-64 g/cm(2)) despite a similar increase in F(ratio), indicating increased Ca(2+) sensitivity in vascular smooth muscle; (ii) nifedipine attenuated this enhanced response by only a maximum of 27% at 1 micromol/l with a 56% reduction in F(ratio); (iii) Y-27632 attenuated it by a maximum of 80% at 100 micromol/l without a significant change in F(ratio); (iv) RhoA protein and mRNA expression levels in the femoral artery were up-regulated by +110% and +56%, respectively, while those of Rho-kinase were unchanged. CONCLUSIONS The Ca(2+)-sensitizing mechanism involving the Rho/Rho-kinase system may be deeply involved in the enhanced arterial vasoconstriction seen in HF. Since Y-27632 attenuated this response in small arteries, it shows potential as a novel, potent vasodilator for the treatment of HF.
Journal of the American College of Cardiology | 2002
Masahiro Doi; Masafumi Yano; Shigeki Kobayashi; Masateru Kohno; Masae Suetsugu; Takahiro Tokuhisa; Shinichi Okuda; Tomoko Ohkusa; Michihiro Kohno; Masunori Matsuzaki
Background. In head failure, hyperphosphorylation of ryanodine receptor (RyR) mediated through PKA has been shown to cause dissociation of FKBP12.6 from RyR, resulting in an abnormal Ca 2+ leak through RyR and possibly consequent cardiac dysfunction. Here, we assessed whether ~-blookede can restore this defective channel function of RyR and therefore improve cardiac function in heart failure. Methods and Results, Sarcoplasmic retioulum (SR) was isolated from dog LV muscles {normal (N), n=5; 4-weeks RV pacing with or without propranolol [P(+): n=4, P(-): n=5, respectively]}. In normal dogs, the dose of propranolol (0.05 mg/kg/day, iv) decreased head rate at baseline by 14 %, but did not attenuate the isoproterenol (0.8 pg/kg/min)-induced increase in peak +dP/ dt of LV pressure. 1) As compared with pre-RV pacing, both end-diastolic [36.2mm in P(+) versus 41.9mm in P(-), p<0.05] and end-systolic diameter [29.4mm in P(+) versus 37.5mm in P(-), p<0.05] were less increased in P(+) than P(-), associated with lesser decrease in fractional shortening [19.0% in P(+) versus 10.2% in P(-), p<0.05]. 2) In SR from P(-), a prominent Ca 2+ leak was observed and FK506 that dissociates FKBP12.6 from RyR did not induce further Ca 2+ leak because of a partial loss of FKBP12.6 from RyR. However, there was no appreciable Ca 2+ leak in SR from P(+), and FK506-inducad Ca 2+ leak was elicited like normal SR. 3) RyR was labeled in a sita-directed fashion with the fluorescent conformational probe methylcoumadn acetate (MCA). In SR from P(+), the FK506-inducad increase in MCA fluorescence, which was virtually absent in SR from P(-), was observed like in normal SR. 4) Indeed, both stoichiometry of FKBP12.6 versus RyR assessed by [3H]FKS06 and [3H]ryanodine-binding assays [3.6 : 1 in N, 1.1 : 1 in P(), 2.4 : 1 in P(+); p<0.05] and protein expression of FKBP12.6 assessed by Western Blot analysis were restored towards those in normal SR. Conclusions. Low dose of propranolol attenuated LV remodeling presumably by ameliorating the defective interaction of FKBP12.6 with RyR, presumably resulting in an inhibition of intracallular Ca 2+ overload and hence a prevention of the development of heart failure.
Circulation | 2002
Masahiro Doi; Masafumi Yano; Shigeki Kobayashi; Masateru Kohno; Takahiro Tokuhisa; Shinichi Okuda; Masae Suetsugu; Yuhji Hisamatsu; Tomoko Ohkusa; Michihiro Kohno; Masunori Matsuzaki
Japanese Circulation Journal-english Edition | 2003
Masafumi Yano; Masahiro Doi; Tetsuro Oda; Shinichi Okuda; Takahiro Tokuhisa; Masae Suetsugu; Tomoko Ohkusa; Masunori Matsuzaki
Japanese Circulation Journal-english Edition | 2003
Shinichi Okuda; Masafumi Yano; Masahiro Doi; Masateru Kohno; Tetsuro Oda; Takahiro Tokuhisa; Masae Suetsugu; Shigeki Kobayashi; Ken Yamamoto; Michihiro Kohno; Tomoko Ohkusa; Masunori Matsuzaki
Journal of Molecular and Cellular Cardiology | 2002
Shinichi Okuda; Masafumi Yano; Shigeki Kobayashi; Masahiro Doi; Masateru Kohno; Takeshi Yamamoto; Tetsuro Oda; Takahiro Tokuhisa; Masae Suetsugu; Tomoko Ohkusa; Masunori Matsuzaki
Japanese Circulation Journal-english Edition | 2002
Masateru Kohno; Masafumi Yano; Shigeki Kobayashi; Masahiro Doi; Masae Suetsugu; Takahiro Tokuhisa; Shinichi Okuda; Tomoko Ohkusa; Michihiro Kohno; Masunori Matsuzaki
Japanese Circulation Journal-english Edition | 2002
Masafumi Yano; Shigeki Kobayashi; Masateru Kouno; Masahiro Doi; Takahiro Tokuhisa; Shinichi Okuda; Masae Suetsugu; Tomoko Ookusa; Michihiro Kouno; Masunori Matsuzaki