Background-Obesity is a major risk factor for the development of cardiovascular disease. Emerging evidence indicates that leptin, a protein encoded by the obesity gene, is linked with cardiac hypertrophy in obese humans and directly induces cardiomyocyte hypertrophy in vitro. However, the mechanisms by which leptin induces cardiomyocyte hypertrophy are poorly understood. Methods and Results-This study investigated how leptin contributes to cardiomyocyte hypertrophy. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of leptin on hypertrophy. Both endothelin-1 (ET-1) and reactive oxygen species (ROS) levels were elevated in a concentration-dependent manner in cardiomyocytes treated with leptin for 4 hours compared with those cells without leptin treatment. ET-1 stimulated ROS production in a concentrationdependent manner in cardiomyocytes. The augmentation of ROS levels in cardiomyocytes treated with both leptin and ET-1 was reversed by a selective ET A receptor antagonist, ABT-627, and catalase, a hydrogen peroxide-decomposing enzyme. After treatment for 72 hours, leptin or ET-1 concentration-dependently increased total RNA levels, cell surface areas, and protein synthesis in cardiomyocytes, all of which were significantly inhibited by ABT-627 or catalase treatment. Conclusions-These findings indicate that leptin elevates ET-1 and ROS levels, resulting in hypertrophy of cultured neonatal rat cardiac myocytes. The ET-1-ET A -ROS pathway may be involved in cardiomyocyte hypertrophy induced by leptin. ET A receptor antagonists and antioxidant therapy may provide an effective means of ameliorating cardiac dysfunction in obese humans.

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Multilevel programing and charge transport characteristics of intrinsic SiOx-based resistive switching memory are investigated using TaN/SiOx/n++Si (MIS) and TiW/SiOx/TiW (MIM) device structures. Current transport characteristics of high- and low-resistance states (HRS and LRS) are studied in both device structures during multilevel operation. Analysis of device thermal response demonstrates that the effective electron energy barrier is strongly dependent on the resistance of the programed state, with estimates of 0.1 eV in the LRS and 0.6 eV in the HRS. Linear data fitting and conductance analyses indicate Poole-Frenkel emission or hopping conductance in the low-voltage region, whereas Fowler-Nordheim (F-N) or trap-assisted tunneling (TAT) is indicated at moderate voltage. Characterizations using hopping transport lead to hopping distance estimates of ∼1 nm in the LRS for both device structures. Relative permittivity values (εr) were extracted using the Poole-Frenkel formulism and estimates of local filament temperature, where εr values were ∼80 in the LRS and ∼4 in the HRS, suggesting a strongly polarized medium in the LRS. The onset of F-N tunneling or TAT corresponds to an observed “overshoot” in the I-V response with an estimated threshold of 1.6 ± 0.2 V, in good agreement with reported electro-luminescence results for LRS devices. Resistive switching is discussed in terms of electrochemical reactions between common SiO2 defects, and specific defect energy levels are assigned to the dominant transitions in the I-V response. The overshoot response in the LRS is consistent with TAT through either the Eγ' oxygen vacancy or the hydrogen bridge defect, both of which are reported to have an effective bandgap of 1.7 eV. The SET threshold at ∼2.5 V is modeled as hydrogen release from the (Si-H)2 defect to generate the hydrogen bridge, and the RESET transition is modeled as an electrochemical reaction that re-forms (SiH)2. The results provide further insights into charge transport and help identify potential switching mechanisms in SiOx-based unipolar resistive switching memory.