Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca 2+ -permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H 2 O 2 ) evokes Ca 2+ influx through TRPM2 to activate Ca 2+ -dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-κB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H 2 O 2 -induced Ca 2+ influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca 2+ influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.
These findings indicate that neutrophil TRPM2 is implicated in the exacerbation of myocardial reperfusion injury. Accumulation of neutrophils in the reperfused area mediated by TRPM2 activation is likely to play a crucial role in myocardial I/R injury.
This study examined whether intravenous administration of tetrahydrobiopterin (BH4) reduces myocardial infarct size following ischemia/reperfusion (I/R) in rats, and the mechanisms of its protective effect were also investigated. Rats were subjected to 30 minutes of ischemia by ligation of the left coronary artery and 2 hours of reperfusion. The infarct size was determined as a percentage of the area at risk by triphenyltetrazolium staining. Intravenous administration of BH4 (0.01 mg/kg-1 mg/kg) significantly reduced the myocardial infarct size. Nitrite plus nitrate (NOx) and cGMP levels in the hearts were significantly increased by the treatment with BH4, and the infarct size-limiting effect of BH4 was abolished by the co-administration of NG-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, or 5-hydroxydecanoic acid, a specific inhibitor of mitochondrial ATP-sensitive potassium channel (mitoKATP channel). These findings suggest that BH4 has a cardioprotective effect against I/R in vivo, and its protective effect appeared to be involved in the opening of mitoKATP channels through increased nitric oxide production.
Abstract. Sustained cardiac pressure overload induces mitochondrial dysfunction and apoptosis of cardiomyocytes leading to pathological cardiac hypertrophy and dysfunction. Mitochondrial nitric oxide synthase (NOS) appears to cause uncoupling, which produces reactive oxygen species (ROS) instead of nitric oxide (NO), by a decrease in the cofactor tetrahydrobiopterin (BH4). This study focused on examining the changes in mitochondrial BH4 levels during cardiac pressure overload. Chronic cardiac pressure overload was generated by abdominal aortic banding in rats. Levels of BH4 and its oxidized form were measured in the mitochondria isolated from the left ventricle (LV) and the post-mitochondrial supernatants. Chronic aortic banding increased blood pressure, and induced cardiac hypertrophy and fibrosis. Notably, the BH4 levels were decreased while its oxidized forms were increased in LV mitochondria, but not in the post-mitochondrial supernatants containing the cytosol and microsome. Anti-neuronal NOS antibody-sensitive protein was detected in the cardiac mitochondria. Moreover, continuous administration of BH4 to rats with pressure overload increased mitochondrial BH4 levels and reduced cardiac fibrosis and matrix metallopeptidase activity, but not cardiac hypertrophy. These findings show the possibility that NOS uncoupling by decreased cardiac mitochondrial BH4 levels is implicated, at least in part, in the development of cardiac fibrosis, leading to cardiac dysfunction induced by pressure overload.
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