Calreticulin and the Heart

Abstract

Calreticulin is an endoplasmic Ca²⁺ binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein supports Ca²⁺-dependent signaling events that are critical to cardiomyocyte differentiation and cardiogenesis. The increased expression of calreticulin and endoplasmic reticulum/sarcoplasmic reticulum Ca²⁺ capacity produces cardiomyocytes with enhanced efficiency, and detrimental mechanical stretching of cardiac fibroblasts, leading to cardiac pathology. Deletion of the calreticulin gene in adult cardiomyocytes results in left ventricle dilation, an impaired electrocardiogram, and heart failure. These observations indicate that a well-adjusted endoplasmic reticulum and calreticulin-dependent Ca²⁺ pool in cardiomyocytes are critical for the maintenance of proper cardiac function.

Keywords: calcium; calreticulin; chaperone; endoplasmic reticulum.

Figure 1

Schematic representation of a relationship between the expression of calreticulin and cardiac development. Calreticulin is abundant in the developing heart, and the expression of the calreticulin gene declines during cardiogenesis. In the adult heart, calreticulin is only a minor Ca²⁺ binding protein and calsequestrin is a major SR Ca²⁺ binding and storage protein. Calreticulin deficiency is embryonic lethal in mice. In the adult heart, either an increased abundance of calreticulin or calreticulin deficiency leads to cardiac pathology and heart failure.

Figure 2

ECHO and ECG analyses of hearts with a silenced calreticulin gene in adult cardiomyocytes. Mice with a calreticulin gene containing two loxP sites flanking exons 4–7 [46] were cross-bred with αMHC (myosin heavy chain)-Cre mice (C57BL/6). To delete exons 4–7 and silence the calreticulin gene in cardiomyocytes, mice were fed tamoxifen [33]. (A). Representative M-mode echocardiography (ECHO) images of wild-type and calreticulin knockout (Calr^−/−) hearts from mice fed tamoxifen for 2 weeks (n = 3). (B). Electrocardiogram (ECG) traces of electrical activity in wild-type and calreticulin knockout (Calr^−/−) hearts after 2 weeks of tamoxifen treatment. Representative electrocardiography recording images of hearts from wild-type and Calr^−/− mice fed tamoxifen for 2 weeks (n = 3).

Figure 3

Comparison of wild-type, calreticulin-overexpressing, and Calr^−/− mouse model systems. Data from three mouse models after 2 weeks of tamoxifen treatment to induce the conditional knockout of calreticulin in cardiomyocytes (Calr^−/−) or 3 weeks of tamoxifen treatment for conditional overexpression of calreticulin in cardiomyocytes. (A). QT interval from the ECG data (Figure 2B); (B). percent Ejection Fraction (%EF) from the echocardiogram analysis (Figure 2A); (C). abundance of spliced XBP1 (spXBP1) mRNA, a measure of IRE1α activation and an ER stress sensor (n = 3).