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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2008.08.020 Byline: Rajesh G. Katare (a), Motonori Ando (a)(c), Yoshihiko Kakinuma (a), Mikihiko Arikawa (a), Takemi Handa (a), Fumiyasu Yamasaki (b), Takayuki Sato (a) Abbreviations: ACh, acetylcholine; ATP, adenosine triphosphate; CABG, coronary artery bypass grafting; PTP, permeability transition pore; SS, sham stimulation; VS, vagal stimulation Abstract: In spite of recent advances in coronary interventional therapy, reperfusion injury is still considered to be a major problem in patients undergoing surgical procedures, such as bypass grafting. Here we demonstrate a novel therapeutic strategy against ischemia-reperfusion injury: vagally mediated prevention of reperfusion-induced opening of mitochondrial permeability transition pore. Author Affiliation: (a) Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan (b) Department of Clinical Laboratory, Kochi Medical School, Nankoku, Japan (c) Department of Science and Education, Okayama University, Okayama, Japan Article History: Received 20 September 2007; Revised 16 July 2008; Accepted 8 August 2008 Article Note: (footnote) Supported by a Health and Labor Sciences Research Grant (H14-NANO-002, H16-NANO-005) from the Ministry of Health, Labor, and Welfare of Japan and by a Grant-in-Aid for Scientific Research (15300165, 17790892) from the Ministry of Education, Science, Sports, and Culture of Japan.

Byline: Hajime Otani, Hideyasu Ohmiya, Reiji Hattori, Hirofumi Fujii, Hideki Ninomiya, Masakuni Kido, Hideki Kawaguchi, Motohiko Osako, Hiroji Imamura, Tetsuo Ohta, Shoji Ohkuma Abstract: Objective: Vacuolar H.sup.+-adenosine triphosphatase plays a pivotal role in pH regulation and molecular transport across the vacuolar membranes and is involved in cell proliferation and transformation. In the present study, possible involvement of vacuolar H.sup.+-adenosine triphosphatase in neointimal formation was investigated in an organ culture model of human saphenous vein. Methods and results: Cultured saphenous vein segments developed neointimal formation and marked thickening of the media within 14 days. Neointimal formation and medial thickening were completely inhibited by 10 nmol/L bafilomycin A.sub.1, a selective inhibitor of vacuolar H.sup.+-adenosine triphosphatase, although structurally related macrolide antibiotics FK-506 and erythromycin were without an effect. The neointimal cells were positive for [alpha]-smooth muscle actin and vimentin but negative for desmin, indicative of myofibroblasts. The emergence of myofibroblasts was inhibited, and endothelial cells were preserved in the saphenous vein segments treated with bafilomycin A.sub.1. Uptake of bromodeoxyuridine, a proliferation marker, by myofibroblasts was abrogated in the saphenous vein segments treated with 10 nmol/L bafilomycin A.sub.1. Detection of apoptotic cells by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling concomitant with identification of desmin-expressing smooth muscle cells demonstrated that neointimal myofibroblasts, but not medial smooth muscle cells, that expressed desmin underwent apoptosis by treatment with bafilomycin A.sub.1. Conclusions: These results suggest that vacuolar H.sup.+-adenosine triphosphatase may be involved in myofibroblast growth that contributes to neointimal formation and medial thickening in cultured human saphenous vein. Increased sensitivity of myofibroblasts, but not endothelial cells, and differentiated smooth muscle cells to bafilomycin A.sub.1 may have potential therapeutic implications in the treatment for vein graft disease. (J Thorac Cardiovasc Surg 2000;119:998-1007) Author Affiliation: From the Department of Thoracic and Cardiovascular Surgery,.sup.a Kansai Medical University, Department of Surgery (II),.sup.b School of Medicine, Kanazawa University, and the Laboratory of Biochemistry,.sup.c Department of Molecular and Cell Biology, Faculty of Pharmaceutical Science, Kanazawa University, Kanazawa, Japan Article History: Received 27 July 1999; Revised 7 October 1999; Revised 16 December 1999; Accepted 16 December 1999 Article Note: (footnote) [star] Address for reprints: Hajime Otani, MD, Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570, Japan (E-mail: otanih@takii.kmu.ac.jp ).

Byline: Akira Koike, Toshiaki Akita, Yoshihiro Hotta, Kazumi Takeya, Itsuo Kodama, Mitsuya Murase, Toshio Abe, Junji Toyama Abstract: The effects of 5-(N,N-dimethyl)amiloride, a potent and specific Na.sup.+-H.sup.+ exchange inhibitor, were investigated in isolated perfused rabbit hearts subjected to ischemia and reperfusion. Phosphorus 31-nuclear magnetic resonance spectroscopy was used to monitor intracellular pH, creatine phosphate, [beta]-adenosine triphosphate, and inorganic phosphate. After cardioplegic arrest with St. Thomas' Hospital solution, normothermic (37A* C) global ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl amiloride at 10 [mu]mol/L, which has minimal inotropic and chronotropic effects on the nonischemic heart, was added to the cardioplegic solution. Treatment with dimethyl amiloride reduced the elevation of left ventricular end-diastolic pressure during and after the ischemia and improved the postischemic recovery of developed pressure from 76% [+ or -] 3.2% at 30 minutes of reperfusion in control hearts (n = 6) up to 99% [+ or -] 1.9% in hearts treated with dimethyl amiloride (n = 8). Dimethyl amiloride did not affect the decline in intracellular pH during ischemia for up to 30 minutes but enhanced the intracellular acidosis thereafter. The intracellular pH at the end of ischemia was 6.21 [+ or -] 0.05 in control hearts compared with 5.24 [+ or -] 0.17 in hearts treated with dimethyl amiloride (p < 0.05). During reperfusion, intracellular pH of hearts treated with dimethyl amiloride was less than control for 5 minutes, but subsequent recovery of intracellular pH was similar to control. Treatment with dimethyl amiloride did not affect creatine phosphate breakdown, inorganic phosphate accumulation, and [beta]-adenosine triphosphate depletion during 45 minutes of ischemia. The creatine phosphate resynthesis and inorganic phosphate reduction during reperfusion were also unaffected. These findings suggest that Na.sup.+-H.sup.+ exchange plays an important role not only during reperfusion but also during ischemia for the development of postischemic cardiac dysfunction most likely by inducing primary Na.sup.+ and secondary Ca.sup.2+ overload. Specific Na.sup.+-H.sup.+ exchange inhibitors like dimethyl amiloride would have a potential therapeutic profile in cardiac surgery, especially if added before ischemia. (J THORAC CARDIOVASC SURG 1996;112:765-75) Article History: Received 24 July 1995; Revised 14 November 1995; Revised 2 April 1996; Accepted 3 April 1996 Article Note: (footnote) [star] From the Department of Thoracic Surgery, School of Medicine, Nagoya University,a Nagoya, Japan; the Department of Pharmacology, Aichi Medical University,b Aichi, Japan; and the Departments of Circulation and Humoral Regulation,c Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan., [star][star] Address for reprints: Itsuo Kodama, MD, Department of Humoral Regulation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-01, Japan., a 0022-5223/96 $5.00 + 0, aa 12/1/73914

Byline: Stanley K.C. Tam, Wei Gu, Bernardo Nadal-Ginard Abstract: In this study, we evaluated the feasibility of converting cardiac fibroblasts into skeletal muscle cells by forced expression of the MyoD gene, one of the basic helix-loop-helix myogenic factors. Primary cardiac fibroblasts, isolated from newborn rats, were infected with retrovirus-carrying sense or antisense MyoD gene. Ten days after infection, expression of MyoD protein was demonstrated in 95% of cells infected with sense MyoD virus by intense nuclear immunostaining with a MyoD polyclonal antibody. In contrast, none of the cells infected with antisense MyoD virus showed staining. On withdrawal of serum, 95% of MyoD positive cells became elongated and, in the presence of appropriate cell density, fused to form multinucleated myotubes, morphologically similar to striated muscle cell. Expression of downstream myogenic differentiation markers, myosin heavy chain and myocyte-specific enhancer factor 2, in 95% of these myotubes were detected by intense cytoplasmic and nuclear immunostaining, respectively, with specific antibodies. In contrast, no detectable staining was noted in MyoD negative cells. Spontaneous contractile movements were noted in a few clusters of myotubes. In summary, cardiac fibroblasts were able to be converted into bonafide potentially functional skeletal myocytes as shown by definitive morphologic and biochemical changes. Further studies with in vivo models are needed to explore this unique molecular strategy to treat patients with chronic heart failure. (J THORAC CARDIOVASC SURG 1995;109:918-24) Author Affiliation: Boston, Mass. Article Note: (footnote) [star] Sponsored by Gus J. Vlahakes, MD, Boston, Mass., [star][star] From the Cardiac Surgical Unit, Massachusetts General Hospital, the Department of Cardiology, The Children's Hospital, and the Departments of Surgery and Pediatrics, Harvard Medical School, Boston, Mass., a Read at the Seventy-fourth Annual Meeting of The American Association for Thoracic Surgery, New York, N.Y., April 24-27, 1994., aa Address for reprints: Stanley K.C. Tam, MD, 300 Mount Auburn St. Suite 516, Cambridge, MA 02138, acents 0022-5223/95 $3.00 + 0, acentsacents 12/6/61883