PICOT (PKC-interacting cousin of thioredoxin) was previously shown to inhibit the development of cardiac hypertrophy, concomitant with an increase in cardiomyocyte contractility. To explore the physiological function of PICOT in the hearts, we generated a PICOT-deficient mouse line by using a gene trap approach. PICOT −/− mice were embryonic lethal indicating that PICOT plays an essential role during embryogenesis, whereas PICOT +/− mice were viable with no apparent morphological defects. The PICOT protein levels were reduced by about 50% in the hearts of PICOT +/− mice. Significantly exacerbated cardiac hypertrophy was induced by pressure overload in PICOT +/− mice relative to that seen in wild type littermates. In line with this observation, calcineurin-NFAT signaling was greatly enhanced by pressure overload in the hearts of PICOT +/− mice. Cardiomyocytes from PICOT +/− mice exhibited significantly reduced contractility, which may be due in part to hypophosphorylation of phospholamban and reduced SERCA activity. These data indicate that the precise PICOT protein level significantly affects the process of cardiac hypertrophy and cardiomyocyte contractility. We suggest that PICOT plays as a critical negative regulator of cardiac hypertrophy and a positive inotropic regulator.
Cucurbitacin I is a naturally occurring triterpenoid derived from Cucurbitaceae family plants that exhibits a number of potentially useful pharmacological and biological activities. However, the therapeutic impact of cucurbitacin I on the heart has not heretofore been reported. To evaluate the functional role of cucurbitacin I in an in vitro model of cardiac hypertrophy, phenylephrine (PE)-stimulated cardiomyocytes were treated with a sub-cytotoxic concentration of the compound, and the effects on cell size and mRNA expression levels of ANF and β-MHC were investigated. Consequently, PE-induced cell enlargement and upregulation of ANF and β-MHC were significantly suppressed by pretreatment of the cardiomyocytes with cucurbitacin I. Notably, cucurbitacin I also impaired connective tissue growth factor (CTGF) and MAPK signaling, pro-hypertrophic factors, as well as TGF-β/Smad signaling, the important contributing factors to fibrosis. The protective impact of cucurbitacin I was significantly blunted in CTGF-silenced or TGF-β1-silenced hypertrophic cardiomyocytes, indicating that the compound exerts its beneficial actions through CTGF. Taken together, these findings signify that cucurbitacin I protects the heart against cardiac hypertrophy via inhibition of CTGF/MAPK, and TGF- β/Smad-facilitated events. Accordingly, the present study provides new insights into the defensive capacity of cucurbitacin I against cardiac hypertrophy, and further suggesting cucurbitacin I’s utility as a novel therapeutic agent for the management of heart diseases.
Retinal neovascularization in retinopathy of prematurity (ROP) is the most common cause of blindness for children. Despite evidence that hypoxia inducible factor (HIF)-1α -VEGF axis is associated with the pathogenesis of ROP, the inhibitors of HIF-1α have not been established as a therapeutic target in the control of ROP pathophysiology. We investigated the hypothesis that degradation of HIF-1α as a master regulator of angiogenesis in hypoxic condition, using β-lapachone, would confer protection against hypoxia-induced retinopathy without affecting physiological vascular development in mice with oxygen-induced retinopathy (OIR), an animal model of ROP. The effects of β-lapachone were examined after intraocular injection in mice with OIR. Intraocular administration of β-lapachone resulted in significant reduction in hypoxia-induced retinal neovascularization without retinal toxicity or perturbation of developmental retinal angiogenesis. Our results demonstrate that HIF-1α–mediated VEGF expression in OIR is associated with pathological neovascularization, not physiological angiogenesis. Thus, strategies blocking HIF-1α in the developing eye in the pathological hypoxia could serve as a novel therapeutic target for ROP.
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