|Budget Amount *help
¥70,850,000 (Direct Cost: ¥54,500,000、Indirect Cost: ¥16,350,000)
Fiscal Year 2012: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2011: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2010: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000)
Fiscal Year 2009: ¥20,930,000 (Direct Cost: ¥16,100,000、Indirect Cost: ¥4,830,000)
Fiscal Year 2008: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Reactive oxygen species (ROS), previously established as cause for oxygen toxicity, have been revealed to work as a major mediator in cellular signaling. Oxidative modification of cysteine thiol in the active site of a target protein is involved in this mechanism. We have an interest in the fact that ROS regulate angiotensin type 1 receptor (AT1R) expression levels, and investigated the underlying mechanisms. Pertussis toxin (PTX), a pharmacological inhibitor of receptor-Gi/o protein coupling via ADP-ribosylation of Gα_<i/o> proteins, increases AT1R expression levels through ROS production. PTX was found to increase AT1R density via Toll-like receptor 4-mediated NADPH oxidase activation and subsequent phosphorylation-dependent NF-κB activation. On the other hand, one of inflammatory ligands, ATP, decreases AT1R density through inducible nitric oxide synthase (iNOS)-mediated suppression of NF-κB activity via covalent modification (S-nitrosylation) of NF-κB. The ATP-induced decrease in AT1R density requires direct interaction between NF-κB and iNOS proteins in the cytosol, suggesting that local interaction of NO-generating enzyme with its sensor/effector protein determines the spatio-temporal regulation of NO signaling. Although NO produced via iNOS in the early phase of heart failure contributes to protection of the heart against physical stress, we found that the iNOS-derived NO reacts with intracellular nucleotides (GTP or cGMP) to form electrophilic 8-nitro-cGMP in the later phase of heart failure. We also found that this 8-nitro-cGMP induces cardiac cellular senescence via electrophilic modification (S-guanylation) of Cys-184 on oncogenic H-Ras, a small GTP-binding protein. More interestingly, we revealed that hydrogen sulfide anion (HS-), but not H2S gas, acts as nucleophile, leading to directly guenching electrohpiles, such as 8-nitro-cGMP, resulting in the suppression of heart failure after myocardial infarction via inhibition of cardiac cellular senescence.