OBJECTIVEp66Shc is a redox enzyme that plays an important role in the response of oxidative stress and the p53-dependent apoptosis. The expression level of p66Shc has a negative correlation with the resistance of oxidative stress in vivo and in vitro. We aim to demonstrate the function of p66Shc in pressure overload-induced heart failure.METHODS AND RESULTSThe pressure overload-induced heart failure was induced in mice by transverse aortic constriction (TAC). Cardiac dysfunction was shown by transthoracic echocardiography. Western blot was used to check the protein levels of phosphodiesterase type 5 (PDE5) and ventricular oxidative stress markers. Superoxide dismutase (SOD) mimetic M40401 and PDE5 inhibitor sildenafil were used in the treatment of mice. The deletion of p66Shc attenuated cardiac dysfunction and oxidative stress in pressure overload-induced heart failure. p66Shc deletion also decreased the expression of ventricular oxidative stress markers and enhanced PKG signaling by promoting the expression of PDE5. M40401 and sildenafil attenuated the TAC-induced cardiac dysfunction and oxidative stress in p66Shc overexpression mice.CONCLUSIONSOur findings suggest that p66Shc participates in the regulation of cardiac dysfunction and oxidative stress in TAC-derived pressure overload-induced heart failure in mice, and SOD and PDE5 are molecules downstream of p66Shc in this regulatory process.

2014-10-01·Journal of Molecular and Cellular Cardiology2区 · 医学

QKI deficiency promotes FoxO1 mediated nitrosative stress and endoplasmic reticulum stress contributing to increased vulnerability to ischemic injury in diabetic heart

2区 · 医学

Article

作者: Zheng, Qiangsun ; Ma, Heng ; Jiang, Tiannan ; Lian, Cheng ; Guo, Wangang ; Wang, Haiyan

Hearts of diabetic individuals are susceptible to ischemia/reperfusion (I/R) injury. The RNA-binding protein Quaking (QKI) is known to link intracellular signaling to cellular survival and QKI dysregulation may contribute to human diseases. However, the function of QKI in diabetic hearts remains unknown. The current study attempted to identify new molecular mechanisms that potentially contribute to the susceptibility to ischemic injury in diabetic myocardium. Diabetic ob/ob mice or wild-type C57BL/6J mice were subjected to in vivo myocardial I/R. Myocardial infarct size and apoptosis, QKI5 and FoxO1 expression, nitrosative stress (NS) and ER stress were compared. Knockdown of FoxO1 was obtained by intramyocardial injection of FoxO1 specific small interfering RNA (siRNA, 20μg), and upregulation of QKI5 was acquired by injecting adenovirus encoding-QKI5. Obvious NS stress was observed in the myocardium of ob/ob mice represented by elevated iNOS expression, total NO content and nitrotyrosine content. Administration of 1400W or M40401 partly reduced the caspase-3 activity in ob/ob myocardium encountering I/R (P<0.05). Higher ER stress was also observed represented by increased p-PERK, p-eIF2α and expression of CHOP in ob/ob myocardium. ER stress inhibitor did not affect the excessive NS stress, but partially reduced I/R-induced caspase-3 activity in ob/ob hearts (P<0.05). FoxO1 was overactivated in ob/ob myocardium, and knockdown of FoxO1 attenuated both levels of NS stress and ER stress (P<0.05). Furthermore, QKI5 expression was deficient in ob/ob myocardium. Upregulation of QKI5 diminished FoxO1 expression together with NS and ER stress in ob/ob myocardium, further reducing MI/R injury. Finally, QKI5 overexpression destabilized FoxO1 mRNA in cardiomyocytes. These results suggested that QKI5 deficiency contributed to the overactivation of FoxO1 in ob/ob animals and subsequently magnified nitrosative stress and ER stress, which enhances the ischemic intolerance of diabetic hearts.

2014-05-01·Contrast Media & Molecular Imaging4区 · 医学

Liposome‐encapsulated superoxide dismutase mimetic: theranostic potential of an MR detectable and neuroprotective agent

4区 · 医学

ArticleOA

作者: Bogdanov, Alexei ; Feula, Giancarlo ; Shazeeb, Mohammed Salman

Endogenous manganese based superoxide dismutase (Mn–SOD) provides the primary defense against excess production of potentially toxic superoxide anion (O2–). M40401 is a synthetic enzyme mimetic that has a catalytic activity rate exceeding that of the native SOD enzymes. The presence of a paramagnetic Mn(II) cation in M40401 suggests that the delivery and spatial distribution of this enzyme mimetic in vivo may be directly detectible using magnetic resonance imaging (MRI); however, the cardiotoxicity of Mn(II) severely limits the use of free M40401 in living systems. To deliver M40401 in vivo in amounts sufficient for MRI detection and to limit potential cardiotoxicity, we encapsulated M40401 into 170 nm liposomes composed of phosphatidylcholine and PEGylated phosphatidylethanolamine to achieve extended circulation in the bloodstream. The obtained liposomes efficiently catalyzed superoxide dismutation in vitro. Using 3 T MRI we investigated the biokinetics of liposome‐encapsulated M40401 in mice and found that, in addition to catalyzing superoxide dismutation in vitro, M40401 caused differential and region‐specific enhancement of mouse brain after systemic administration. Thus, liposome encapsulated M40401 is an ideal candidate for development as a theranostic compound useful for simultaneous MRI‐mediated tracking of delivery as well as for neuroprotective treatment of ischemic brain. Copyright © 2014 John Wiley & Sons, Ltd.

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