Preserved cardiomyocyte function and altered desmin pattern in transgenic mouse model of dilated cardiomyopathy.

Taking advantage of the unique model of slowly developing dilated cardiomyopathy in mice with cardiomyocyte-specific transgenic overexpression of activated Gαq protein (Tgαq*44 mice) we analyzed the contribution of the cardiomyocyte malfunction, fibrosis and cytoskeleton remodeling to the development of heart failure in this model. Left ventricular (LV) in vivo function, myocardial fibrosis, cytoskeletal proteins expression and distribution, Ca(2+) handling and contractile function of isolated cardiomyocytes were evaluated at the stages of the early, compensated, and late, decompensated heart failure in 4-, 12- and 14-month-old Tgαq*44 mice, respectively, and compared to age-matched wild-type FVB mice. In the 4-month-old Tgαq*44 mice significant myocardial fibrosis, moderate myocyte hypertrophy and increased expression of regularly arranged and homogenously distributed desmin accompanied by increased phosphorylation of desmin chaperone protein, αB-crystallin, were found. Cardiomyocyte shortening, Ca(2+) handling and LV function were not altered. At 12 and 14 months of age, Tgαq*44 mice displayed progressive deterioration of the LV function. The contractile performance of isolated myocytes was still preserved, and the amplitude of Ca(2+) transients was even increased probably due to impairment of Na(+)/Ca(2+) exchanger function, while fibrosis was more extensive than in younger mice. Moreover, substantial disarrangement of desmin distribution accompanied by decreasing phosphorylation of αB-crystallin appeared. In Tgαq*44 mice disarrangement of desmin, at least partly related to inadequate phosphorylation of αB-crystallin seems to be importantly involved in the progressive deterioration of contractile heart function.

Seasonal superoxide overproduction and endothelial activation in guinea-pig heart; seasonal oxidative stress in rats and humans.

Seasonality in endothelial dysfunction and oxidative stress was noted in humans and rats, suggesting it is a common phenomenon of a potential clinical relevance. We aimed at studying (i) seasonal variations in cardiac superoxide (O(2)(-)) production in rodents and in 8-isoprostane urinary excretion in humans, (ii) the mechanism of cardiac O(2)(-) overproduction occurring in late spring/summer months in rodents, (iii) whether this seasonal O(2)(-)-overproduction is associated with a pro-inflammatory endothelial activation, and (iv) how the summer-associated changes compare to those caused by diabetes, a classical cardiovascular risk factor. Langendorff-perfused guinea-pig and rat hearts generated ~100% more O(2)(-), and human subjects excreted 65% more 8-isoprostane in the summer vs. other seasons. Inhibitors of NADPH oxidase, xanthine oxidase, and NO synthase inhibited the seasonal O(2)(-)-overproduction. In the summer vs. other seasons, cardiac NADPH oxidase and xanthine oxidase activity, and protein expression were increased, the endothelial NO synthase and superoxide dismutases were downregulated, and, in guinea-pig hearts, adhesion molecules upregulation and the endothelial glycocalyx destruction associated these changes. In guinea-pig hearts, the summer and a streptozotocin-induced diabetes mediated similar changes, yet, more severe endothelial activation associated the diabetes. These findings suggest that the seasonal oxidative stress is a common phenomenon, associated, at least in guinea-pigs, with the endothelial activation. Nonetheless, its biological meaning (regulatory vs. deleterious) remains unclear. Upregulated NADPH oxidase and xanthine oxidase and uncoupled NO synthase are the sources of the seasonal O(2)(-)-overproduction.

Brief postinfarction calcineurin blockade affects left ventricular remodeling and Ca2+ handling in the rat.

The role of calcineurin (CN) pathway in the post-myocardial infarction (MI) heart remains unclear. We investigated effects of early and brief inhibition of CN pathway with cyclosporine A (CsA) after MI on both immediate and delayed changes in left ventricular (LV) morphology, haemodynamics, and cardiomyocyte performance. CsA/saline was administered for 4 days, starting 24 h after MI/sham surgery in the rat. MI resulted in CN overactivity, peaking on day 3, accompanied by significant intracellular Ca(2+) overload due to marked decrease of NCX function. On day 7 and in week 8, CN activity decreased and normalized, respectively. It was accompanied by normalization of Ca(2+) handling parameters (only SERCA function was moderately decreased). CsA abolished post-MI CN overactivity, protected against Ca(2+) overload on day 3 and slightly improved SERCA function on day 7. Moreover, CsA reduced hypertrophy on days 3 and 7 after MI, increased wall stress on day 7 and in week 8, and lowered ejection fraction, augmented LV dilation as well increased mortality in week 8. Our study demonstrates that blockade of brief post-MI CN overactivity with CsA has delayed detrimental effects: increased mortality and worse LV function. CsA prevented early cardiomyocyte hypertrophy, decreased wall thickness and thus increased the wall stress, the main stimulus for detrimental LV dilation. Furthermore, CsA treatment prevented early Ca(2+) overload related to decreased NCX function. Role of this early Ca(2+) overload is unclear; it might be an element of positive feedback loop amplifying CN activation in post-MI heart.