No abstract

Rationale In the working heart coronary blood flow is linked to the production of metabolites, which modulate tone of smooth muscle in a redox-dependent manner. Voltage-gated potassium channels, which play a role in controlling membrane potential in vascular smooth muscle, have certain members that are redox sensitive. Objective To determine the role of redox-sensitive Kv1.5 channels in coronary metabolic flow regulation. Methods and Results In mice (wild type [WT], Kv1.5 null [Kv1.5−/−], and Kv1.5−/− and WT with inducible, smooth muscle specific expression of Kv1.5 channels) we measured mean arterial pressure (MAP), myocardial blood flow (MBF), myocardial tissue pO2, and ejection fraction (EF) before and after inducing cardiac stress with norepinephrine (NE). Cardiac work (CW) was estimated as the product of MAP and heart rate. Isolated arteries were studied to establish if genetic alterations modified vascular reactivity. Despite higher levels of CW in the Kv1.5−/− (versus WT at baseline and all doses of NE), MBF was lower in Kv1.5−/− than in WT. At high levels of CW, tissue pO2 dropped significantly along with EF. Expression of Kv1.5 channels in smooth muscle in the null background rescued this phenotype of impaired metabolic dilation. In isolated vessels from Kv1.5−/− mice, relaxation to H2O2 was impaired, but responses to adenosine and acetylcholine were normal compared to WT. Conclusions Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. Absence of these channels disassociates metabolism from flow resulting in cardiac pump dysfunction and tissue hypoxia.

Edited by Varda RotterKeywords: ER stress Rad51 DNA double-strand break repair Radiosensitivity Unfolded protein response a b s t r a c tIn this study, we provide evidence that endoplasmic reticulum (ER) stress suppresses DNA doublestrand break (DSB) repair and increases radiosensitivity of tumor cells by altering Rad51 levels. We show that the ER stress inducer tunicamycin stimulates selective degradation of Rad51 via the 26S proteasome, impairing DSB repair and enhancing radiosensitivity in human lung cancer A549 cells. We also found that glucose deprivation, which is a physiological inducer of ER stress, triggered similar events. These findings suggest that ER stress caused by the intratumoral environment influences tumor radiosensitivity, and that it has potential as a novel target to improve cancer radiotherapy.

bergen C, Gabrielson K. ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity. Am J Physiol Heart Circ Physiol 309: H1271-H1280, 2015. First published August 14, 2015; doi:10.1152/ajpheart.00517.2014.-Levels of the HER2/ErbB2 protein in the heart are upregulated in some women during breast cancer therapy, and these women are at high risk for developing heart dysfunction after sequential treatment with anti-ErbB2/trastuzumab or doxorubicin. Doxorubicin is known to increase oxidative stress in the heart, and thus we considered the possibility that ErbB2 protein influences the status of cardiac antioxidant defenses in cardiomyocytes. In this study, we measured reactive oxygen species (ROS) in cardiac mitochondria and whole hearts from mice with cardiacspecific overexpression of ErbB2 (ErbB2 tg ) and found that, compared with control mice, high levels of ErbB2 in myocardium result in lower levels of ROS in mitochondria (P ϭ 0.0075) and whole hearts (P ϭ 0.0381). Neonatal cardiomyocytes isolated from ErbB2 tg hearts have lower ROS levels and less cellular death (P Ͻ 0.0001) following doxorubicin treatment. Analyzing antioxidant enzyme levels and activities, we found that ErbB2 tg hearts have increased levels of glutathione peroxidase 1 (GPx1) protein (P Ͻ 0.0001) and GPx activity (P ϭ 0.0031) in addition to increased levels of two known GPx activators, c-Abl (P ϭ 0.0284) and Arg (P Ͻ 0.0001). Interestingly, although mitochondrial ROS emission is reduced in the ErbB2 tg hearts, oxygen consumption rates and complex I activity are similar to control littermates. Compared with these in vivo studies, H9c2 cells transfected with ErbB2 showed less cellular toxicity and produced less ROS (P Ͻ 0.0001) after doxorubicin treatment but upregulated GR activity (P ϭ 0.0237) instead of GPx. Our study shows that ErbB2-dependent signaling contributes to antioxidant defenses and suggests a novel mechanism by which anticancer therapies involving ErbB2 antagonists can harm myocardial structure and function.ErbB2; glutathione peroxidase; reactive oxygen species; nRTK; mitochondria NEW & NOTEWORTHY This is the first study on ErbB2 overexpression in the heart that identifies cardioprotection after doxorubicin treatment. Our findings suggest that an adverse effect on redox signaling pathways necessary for maintaining mitochondrial antioxidant defenses may be an important mechanism of cardiac toxicity induced by drugs that target ErbB2 and Abl kinases.THE ERBB2 RECEPTOR TYROSINE kinase is a member of the epidermal growth factor receptor (EGFR) family and has an essential role in cardiac function and development (9,39,47,50). ErbB2 is also important in cancer biology, and dysregulated ErbB2 signaling is implicated in various types of cancer, most notably in breast and ovarian cancer (30, 49). The clinical link between ErbB2 and heart function was discovered when 27% of ErbB2-overexpressing breast cancer patients treated with doxorubicin and anti-...