Abstract P217: Western Diet Promotes Cardiac Diastolic Dysfunction by Increasing Cardiomyocytes Calcium Sensing Receptor via Activation of Parathyroid Hormone, Parathyroid Related Hormone and Their Receptor- 1 in Female Mice

Abstract

Background: Data from our Lab and others indicate that consumption of a western diet (WD), high in fat and refined carbohydrates promotes cardiac hypertrophy and diastolic dysfunction. Recently, a role for calcium sensing receptor (CaSR) and the fibroblast growth factor 23 (FGF 23)/ Klotho axis has been increasingly recognized in the pathogenesis of cardiac hypertrophy and diastolic dysfunction. However, the role of these factors in WD induced cardiac dysfunction has not been elucidated. Therefore, the purpose of this study was to determine mechanisms and signaling pathways underlying WD-induced cardiac diastolic dysfunction in female C57-Bl6/J mice. Methods and Results: Four week-old female C57-BL6/J mice were fed a control diet (CD) or WD containing fat (46%) and fructose (17.5%) for 16 weeks. Then, left ventricular (LV) and serum were harvested and processed for immunohistochemistry and serum analysis. Four μm paraffin embedded sections of the LV were incubated with primary antibodies (CaSR), parathyroid hormone (PTH), parathyroid related hormone (PTHrP), parathyroid hormone receptor-1 (PHTR-1), parathyroid hormone receptor-2 (PHTR-2), (FGF23), klotho and appropriate secondary antibodies. Images were captured with a bi-photon confocal microscope and signal intensities were quantified as gray scale intensities. Analysis of immunofluorescence images revealed that consumption of a WD resulted in significantly higher expression level of CaSR, PTH, PTHrP, PTHR-1 and FGF23. Also, consumption of WD significantly increased the serum PTH level. Furthermore, analysis of WGA stained images showed significant hypertrophy of LV cardiomyocytes. Interestingly, WD did not increase the expression of PTHR-2 and Klotho in LV but levels of this protein in the coronary arteries. Conclusion: These findings support the preliminary notion that there is a role of PTH, PTHR-1 and PTHrP signaling in dietary promotion of cardiomyocytes hypertrophy and diastolic dysfunction. These effects could be mediated via modulation of cardiac calcium metabolism.