cardiomyocyte contractile dysfunction in the appsweps1de9 mouse model of alzheimers disease心肌细胞的收缩功能障碍appsweps1de9阿尔茨海默病小鼠模型.pdfVIP

Cardiomyocyte Contractile Dysfunction in the APPswe/ PS1dE9 Mouse Model of Alzheimer’s Disease Subat Turdi, Rui Guo, Anna F. Huff, Eliza M. Wolf, Bruce Culver, Jun Ren* Division of Pharmaceutical Sciences Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, Wyoming, United States of America Abstract Objectives: Ample clinical and experimental evidence indicated that patients with Alzheimer’s disease display a high incidence of cardiovascular events. This study was designed to examine myocardial histology, cardiomyocyte shortening, intracellular Ca2+ homeostasis and regulatory proteins, electrocardiogram, adrenergic response, endoplasmic reticulum (ER) stress and protein carbonyl formation in C57 wild-type (WT) mice and an APPswe/PS1dE9 transgenic (APP/PS1) model for Alzheimer’s disease. Methods: Cardiomyocyte mechanical properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to- relengthening (TR), maximal velocity of shortening and relengthening (6dL/dt), intracellular Ca2+ transient rise and decay. Results: Little histological changes were observed in APP/PS1 myocardium. Cardiomyocytes from APP/PS1 but not APP or PS1 single mutation mice exhibited depressed PS, reduced6dL/dt, normal TPS and TR compared with WT mice. Rise in intracellular Ca2+ was lower accompanied by unchanged resting/peak intracellular Ca2+ levels and intracellular Ca2+ decay in APP/PS1 mice. Cardiomyocytes from APP/PS1 mice exhibited a steeper decline in PS at high frequencies. The responsiveness to adrenergic agonists was dampened although b1-adrenergic receptor expression was unchanged in APP/PS1 hearts. Expression of the Ca2+ regulatory protein phospholamban and protein carbonyl formation were downre