Background: Autophagy activity is reduced in type 1 diabetic heart, but the functional role remains unclear. Results: Further reduction in autophagy protects against diabetic heart injury, whereas restoration of autophagy exacerbates cardiac damage. Conclusion:The diminished autophagy limits cardiac dysfunction in type 1 diabetes. Significance: Understanding the functional role of autophagy will facilitate drug design to fight diabetic heart disease.

Doxorubicin (DOX) is a potent anti-tumor drug known to cause heart failure. The transcription factor GATA4 antagonizes DOX-induced cardiotoxicity. However, the protective mechanism remains obscure. Autophagy is the primary cellular pathway for lysosomal degradation of long-lived proteins and organelles, and its activation could be either protective or detrimental depending on specific pathophysiological conditions. Here we investigated the ability of GATA4 to inhibit autophagy as a potential mechanism underlying its protection against DOX toxicity in cultured neonatal rat cardiomyocytes. DOX markedly increased autophagic flux in cardiomyocytes as indicated by the difference in protein levels of LC3-II (microtubule-associated protein light chain 3 form 2) or numbers of autophagic vacuoles in the absence and presence of the lysosomal inhibitor bafilomycin A1. DOX-induced cardiomyocyte death determined by multiple assays was aggravated by a drug or genetic approach that activates autophagy, but it was attenuated by manipulations that inhibit autophagy, suggesting that autophagy contributes to DOX cardiotoxicity. DOX treatment depleted GATA4 protein levels, which predisposed cardiomyocytes to DOX toxicity. Indeed, GATA4 gene silencing triggered autophagy that rendered DOX more toxic, whereas GATA4 overexpression inhibited DOX-induced autophagy, reducing cardiomyocyte death. Mechanistically, GATA4 up-regulated gene expression of the survival factor Bcl2 and suppressed DOX-induced activation of autophagy-related genes, which may likely be responsible for the anti-apoptotic and anti-autophagic effects of GATA4. Together, these findings suggest that activation of autophagy mediates DOX cardiotoxicity, and preservation of GATA4 attenuates DOX cardiotoxicity by inhibiting autophagy through modulation of the expression of Bcl2 and autophagy-related genes. Doxorubicin (DOX)4 is a very effective anti-cancer drug with cardiotoxicity that culminates in congestive heart failure (1-3).The prevailing mechanism for DOX cardiotoxicity is oxidative stress that has been supported by the ability of several antioxidants to reduce DOX cardiotoxicity in animal studies (4 -8). Unfortunately, clinical trials have failed to reproduce these results in humans (9), suggesting that mechanisms other than oxidative stress might also contribute to DOX-induced heart failure (9 -13). In support of this notion, DOX has been shown to cause cardiac mitochondrial injury by both oxidative and non-oxidative mechanisms (14).Autophagy is the major cellular pathway for degrading and recycling long-lived proteins and organelles that are sequestered in double-membrane vesicles termed autophagosomes. After fusing with the lysosome to form autolysosome, the inner membrane and the contents are degraded and recycled. More than 30 autophagy-related (ATG) genes encode proteins essential for autophagy induction and the generation, maturation, and recycling of autophagosomes or autophagic vacuoles (15,16). Autophagy has long been recognized to provide a survival pathw...

The diagnosis of cancer elicits a broad range of well-characterized stress-related biobehavioral responses. Recent studies also suggest that an individual’s neuroendocrine stress response can influence tumor biology. One of the major physiological pathways altered by the response to unrelenting social stressors is the hypothalamic–pituitary–adrenal or HPA axis. Initially following acute stress exposure, an increased glucocorticoid response is observed; eventually, chronic stress exposure can lead to a blunting of the normal diurnal cortisol pattern. Interestingly, recent evidence also links high primary tumor glucocorticoid receptor expression (and associated increased glucocorticoid-mediated gene expression) to more rapid estrogen-independent breast cancer progression. Furthermore, animal models of human breast cancer suggest that glucocorticoids inhibit tumor cell apoptosis. These findings provide a conceptual basis for understanding the molecular mechanisms underlying the influence of the individual’s stress response, and specifically glucocorticoid action, on breast cancer and other solid tumor biology. How this increased glucocorticoid signaling might contribute to cancer progression is the subject of this review.