HomeHypertensionVol. 76, No. 6Tomoh Masaki Free AccessObituaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessObituaryPDF/EPUBTomoh Masaki Noriaki Emoto Masashi Yanagisawa Matthias Barton Noriaki EmotoNoriaki Emoto Correspondence to Noriaki Emoto, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan, Email E-mail Address: [email protected] https://orcid.org/0000-0001-6673-2616 Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, Kobe, Japan, International Advisory Board (IAB), International Conferences on Endothelin Search for more papers by this author Masashi YanagisawaMasashi Yanagisawa Masashi Yanagisawa, International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan, Email E-mail Address: [email protected] https://orcid.org/0000-0002-8200-4341 International Institute for Integrative Sleep Medicine (WPI-IIIS), Life Science Center for Survival Dynamics (TARA), R&D Center for Frontiers of Mirai in Policy and Technology (F-MIRAI), University of Tsukuba, Tsukuba, Japan, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, International Advisory Board (IAB), International Conferences on Endothelin Search for more papers by this author Matthias BartonMatthias Barton Matthias Barton, Molecular Internal Medicine, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland, Email E-mail Address: [email protected]. https://orcid.org/0000-0002-8200-4341 Molecular Internal Medicine, University of Zürich, Andreas Grüntzig Foundation, Zürich, Switzerland, International Advisory Board (IAB), International Conferences on Endothelin Search for more papers by this author Originally published11 Nov 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.15935Hypertension. 2020;76:1664–1666…I cannot follow the recent advances in ET research.I only enjoy it.—Tomoh Masaki (2011)Download figureDownload PowerPointTomoh MasakiProfessor Tomoh Masaki was a Japanese physician, scientist, teacher, mentor, husband, and father, who died on July 7, 2020, after a prolonged illness, at the age of 85 years.Professor Masaki made scientific history by discovering and cloning endothelins and their receptors.1–3 His discoveries paved the way for the development of a new class of drugs, the endothelin receptors antagonists, which are now firmly established in the treatment of pulmonary arterial hypertension and digital ulcers in systemic sclerosis.4Endothelins are potent endothelial cell–derived peptides with cytokine-like activity that are involved in almost all aspects of cell function and have been causally implicated in numerous chronic noncommunicable diseases.4 They were discovered a few years after Robert F. Furchgott’s (1916–2009) discovery of the release of an EDRF (endothelium-derived relaxing factor) later identified as NO,5 and Paul M. Vanhoutte (1940–2019) had described the release of endothelium-derived vasoconstricting factors.6,7Masaki was born on October 26, 1934, in Tokyo where he grew up during the Second World War. He graduated from the Faculty of Medicine of the University of Tokyo in 1962 and after completing his clinical internship obtained a PhD at the same institution under the guidance of renowned pharmacologist Professor Setsuro Ebashi. Masaki’s initial research focused on mechanisms of muscular contraction, including calcium and muscular proteins such as different types of myosin and troponin, which led to the discovery of α-actinin and M-protein.8 In 1975, Masaki was appointed Professor of Pharmacology at the University of Tsukuba where he made several seminal discoveries.1,9He subsequently became Vice Dean of the University of Tsukuba Medical School and dedicated much of his time to research and education of medical students. In 1991, Masaki moved to the University of Kyoto where he and his associates identified the endothelial receptor for oxidized low-density lipoprotein,10 and in 1997, he was appointed Director of the Research Institute of the National Cardiovascular Center in Osaka. In 2003, Masaki became President of Osaka Seikei University. He was appointed Professor at Tokyo Women’s Medical University in 2007 from where he retired in 2009.In early 1987, during a journal club, University of Tsukuba cardiology fellow Hiroki Kurihara, who was studying full-time in the Masaki laboratory, presented a paper that was the result of a collaboration between 2 groups at the Department of Physiology and Biophysics of the University of Cincinnati Medical School, with Kristine Hickey (née Agricola) and Gabor Rubanyi working in the laboratories of Robert Highsmith and Richard Paul, respectively.1,11 In 1982, these investigators had discovered the activity of a novel endothelial cell–derived peptidergic vasoconstrictor12 in search of the chemical nature of the EDRF reported by Furchgott.11,13 Hickey generated media conditioned from cultured endothelial cells, which Rubanyi, using bioassay experiments, applied to isolated vascular strips expecting to evaluate smooth muscle relaxation; however, there was no relaxation but rather, persistent constriction.11 The investigators also found that the contractile activity was caused by a polypeptide, which they named endotensin.11,13 They determined its approximate molecular weight and submitted a manuscript to Science where it was rejected (Gabor Rubanyi, personal communication). In October 1984, the manuscript was submitted to the American Journal of Physiology where it was published in the May issue of the following year.13,14Two years later, in March 1987, graduate student Masashi Yanagisawa, who had joined Masaki’s laboratory after completing medical school in 1985, proposed to Professor Masaki to identify this vasoconstrictor substance as his PhD project. Masaki agreed and first engaged pharmacologist Katsutoshi Goto (1943–2017). After Yanagisawa had confirmed the vasoconstrictor activity of endothelial cell–conditioned medium (Figure), Masaki also involved peptide chemist Sadao Kimura in the project.15,16 Professor Masaki once summarized his most important discovery in his own words:Download figureDownload PowerPointFigure. Original tracing of the first vascular contraction to endothelin-1 ever obtained by Masashi Yanagisawa in March 1987 while working in Professor Masaki’s group as his graduate student at the University of Tsukuba, Japan. The contraction was evoked in a porcine coronary artery ring connected to a force transducer suspended in an organ bath filled with physiological salt solution by exposing the ring to increasing concentrations (10% and 20%) of porcine coronary artery endothelial cell–conditioned medium (EM) containing the secreted endothelin-1 peptide. Note that the contraction continued and hardly decreased even after replacing the salt solution. The potent and sustained contraction continued for more than half an hour, and relaxation of the coronary artery ring could only be achieved by adding isoproterenol to the organ bath solution. FM indicates fibroblast-conditioned medium; KCl, potassium chloride; UM, unconditioned medium; and W, wash (replacing organ bath solution with physiological salt solution).Drs. Yanagisawa, Kurihara, Goto, and Kimura were the initial participants in the project. The group finished the purification of this peptide by the end of July 1987. The initial sequence analysis was carried out in collaboration with Applied Biosystem Co. Ltd., because the university had no peptide sequencer at that time. The whole sequence, except five residues, was determined by the middle of August. Dr. Kimura (peptide chemist, who discovered neurokinin earlier) suggested that the undetermined residues were cysteines. The sequence was reanalyzed on a new apparatus at the National Institute of Basic Biology in Okazaki. The whole sequence was determined by the next day. Dr. Yanagisawa meanwhile performed mRNA preparation from endothelial cells and also cDNA cloning and determined the whole sequence of the preproform of the peptide within 3 weeks. At the end of August 1987 a 20 amino acid peptide was synthesized by collaborating scientists at the Takeda Pharmaceutical Company. However, this peptide had no biological activity. New amino acid analysis by Dr. Kimura revealed the existence of Trp at position 21 in the peptide sequence. The 21 residue peptide had a molecular weight of 2492 Da […]. It was synthesized, which matched the native peptide both chemically and pharmacologically. It was the end of October 1987 when the peptidergic EDCF was isolated, purified, sequenced, and synthesized. It was named endothelin, and the paper describing it was sent to and later published in Nature.17Notably, the vast amount of experimental work was completed within only 5 months. The manuscript was submitted in November 1987 and published in the March 31, 1988, issue of Nature.1Throughout his career, Professor Masaki has been honored with prizes and awards. For the discovery of endothelins, Professor Masaki in 1990 received The Second Tsukuba Prize consisting of a large silver medal and a research award of ¥5 million (≈150 000 USD at the time).18 Masaki has been the recipient of the Japan Medical Association Award, the Takeda Medical Prize, the Asahi Prize, the Japan Academy Prize, the Medal of Honor, the Cultural Merit Award, the Order of the Sacred Treasure, and many others distinctions. In 2011, the International Advisory Board of the International Conferences on Endothelin inaugurated an award in his name to honor Professor Masaki’s pioneering achievements and to recognize his service and his contributions to science and medicine.18Professor Masaki was a hard-working, humble, and warm-hearted man who much enjoyed life. His former students (N.E. and M.Y.) remember him as somebody much outside the ordinary, who with enormous kindness captivated people through his personality, his purity, and clarity as someone whose sole goal was to search and find scientific truth. Though his career was focused on basic science, pharmacology, and molecular biology; he was always interested in the potential clinical significance and application that his work would have. Professor Masaki frequently gave parties for his laboratory staff—sometimes held under cherry blossoms—participating in singing traditional Japanese folk songs.18 He was a great mentor to his students and fellows, encouraging them to think freely and independently and supporting and helping them with their careers.18 Indeed, the laboratory was approvingly nicknamed “Masaki Open Pasture” by colleagues. Professor Masaki took great joy in his main scientific achievement until late in his life, which is also reflected in the above quote made less than a decade ago.18Professor Masaki was a uniquely gifted and curious physician-scientist. His legacy in science and medicine is substantial; his discoveries allowed for the development of a new class of orally active drugs, the endothelin receptor antagonists, which have been available to patients with pulmonary arterial hypertension for almost 20 years.4 Professor Masaki leaves behind his wife and his 2 sons. He left a mark on science and will always be remembered for his innovative and truly pioneering research. Throughout his career, he has touched many lives, and he will not be forgotten. His work continues to this day in laboratories he impacted across the world. Our thoughts are with Mrs Masaki and her family.FootnotesCorrespondence to Noriaki Emoto, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan, Email [email protected]kobe-u.ac.jpMasashi Yanagisawa, International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan, Email yanagisawa.masa.[email protected]tsukuba.ac.jpMatthias Barton, Molecular Internal Medicine, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland, Email [email protected]uzh.ch.