Ca2+ plays fundamental roles in the cell as a secondary messenger, being involved in the regulation of many processes including signal transduction, contraction, gene expression and blood coagulation. The proteins involved in Ca2+-regulated processes in the cytosol are mainly high-affinity Ca2+-binding proteins, in general with EF-hand motifs. Calumenin is a multiple EF-hand protein located in ER/SR of mammalian heart and other tissues and is known to have inhibitory effect on the vitamine K-dependent-carboxylation system. To elucidate the role of calumenin in the heart, transgenic (TG) mice overexpressing the mouse calumenin under the control of mouse αMHC promoter were generated.
Overexpression (20-fold) of calumenin was associated with concentric LV hypertrophy with preserved systolic function and bradycardia. In some TG mice, biatrial enlargement with intraatrial thrombi and biventricular hypertrophy was observed. Interestingly, petechias were seen on the surface of ventricle and/or atria and spontaneous hemopericardium was observed in few TG mice. HW/BW ratio (4.34±0.94) of TG heart was greater than that (3.86±0.21) of their littermates and RV weight was significantly greater that WT (p<0.05). Although LV dimension and fractional shortening was not different, IVS and LVPW was significantly thicker and LV mass (116.3±45.7g) of TG heart was significantly increased compared to WT (82.9±11.4g, p<0.05). HR (381±40/min) of TG mice was less than that (494±46/min) of their littermates (p<0.0001). Increased collagen contents and perivascular or interstitial fibrosis were observed microscopically. In TG hearts, the expression levels of E-C coupling proteins such as junctin, triadin, calsequestrin, NaCa+-Ca2+ exchanger were unchanged but phospholamban was upregulated (4.8-fold) in TG heart.
Although those morphological, physiological, electrical and biochemical alterations could be explained by the perturbations of the intracellular Ca2+ homeostasis, further experiments should be followed to dissect the exact mechanism of cardiovascular phenotypes in TG mice and to elucidate the functional role of calumenin.
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