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Cardiocirculatory Signaling

NISHIDA, Motohiro (Prof.)


Establishment of the molecular basis underlying multi-level regulation of cardiocirculatory homeostasis toward understanding the cardiac robustness.

The concept of evidence-based medicine has provided understanding of the systemic control of cardiovascular homeostasis by neurohumoral factors, nutrition factors, and oxygen-derived reactive species. Our pharmacological and pathophysiological studies are based on detailed analyses of two essential signaling mediators, calcium ion (Ca2+) and reactive oxygen species (ROS), to understand multilevel spatio-temporal regulation of context-dependent signaling to create an innovative technology for clinical applications. Specifically, we aim to establish the molecular basis underlying systemic control of cardiac reduction/oxidation (redox) homeostasis through application of chemical techniques and concepts to the study and manipulation of biological system (Figure 1). We also focus on the operating principles of Ca2+-permeable transient receptor potential (TRP) channels to understand the mechanism underlying dynamic maintenance and transfiguration of Ca2+ signaling contexts in the cardiovascular system (Figure 2).

Figure 1.

Figure 1. Putative mechanism of regulation of cardiac redox homeostasis by cardiocirculatory reactive sulfur species (RSS). RSS function as a nucleophile, directly eliminating endogenous electrophiles that are main causes of chronic cardiovascular diseases.

Figure 2.

Figure 2. Control of cardiac homeostasis by the interaction among circulatory organs. A mechano-activated Ca2+-permeable channels (TRPC3/6) activated by hemodynamic load are found to mediate neurohumoral secretions required for circulatory cross-talks among multiple organs.



  1. Nishida M, Sawa T, Kitajima N, Ono K, Inoue H, Ihara H, Motohashi H, Yamamoto M, Suematsu M, Kurose H, van der Vliet A, Freeman BA, Shibata T, Uchida K, Kumagai Y and Akaike T. Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration. Nature Chem. Biol. 8: 714-724 (2012).
  2. Nishioka K, Nishida M, Ariyoshi M, Saiki S, Jian Z, Hirano M, Nakaya M, Sato Y, Kita S, Iwamoto T, Hirano K, Inoue R and Kurose H Protein kinase A-mediated phosphorylation of TRPC6 channels underlies suppression of angiotensin II-induced vasoconstriction. Arterioscler. Thromb. Vasc. Biol. 31: 2278-2286 (2011).
  3. Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim K-M, Ide T, Sato Y, Inoue K and Kurose H Heterologous down-regulation of angiotensin type1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-kB. Proc. Natl. Acad. Sci. USA. 108: 6662-6627 (2011).
  4. Numaga T, Nishida M, Kiyonaka S, Kato K, Katano M, Mori E, Kurosaki T, Inoue R, Hikida M, Putney JW Jr, and Mori Y Ca2+ influx and protein scaffolding via TRPC3 sustain PKCβand ERK activation in B cells. J. Cell Sci. 123: 927-938 (2010).
  5. Nishida M, Sato Y, Uemura A, Narita Y, Tozaki-Saitoh H, Nakaya M, Ide T, Suzuki K, Inoue K, Nagao T & Kurose H P2Y6 Receptor-Ga12/13 Signaling in Cardiomyocytes Triggers Pressure Overload-induced Cardiac Fibrosis. EMBO J. 27: 3104-3115 (2008).


Okazaki Institute for Integrative Bioscience
5-1 Higashiyama Myodaijichou Okazaki Aichi