Calcineurin and cardiac function: is more or less better for the heart?

摘要

calcineurin (CN) is a Ca~(2+)-calmodulin-activated serine-threo-nine phosphatase that is ubiquitously expressed and plays an important role in transducing Ca~(2+)-dependent signals. Cn is a heterodimer composed of calmodulin binding catalytic subunit A (CnA) and a Ca~(2+) binding regulatory subunit B (CnB) (10). More than a decade ago, in 1998, Cn was implicated for the first time in regulation of cardiac hypertrophy (9). Since then, the role of Cn as modulator of cardiac hypertrophy has been the subject of several studies using Cn inhibitors or transgenic mice overexpressing active Cn or Cn inhibiting proteins (for review, see Ref. 15). Most of the studies confirm that Cn plays a critical role in the development of pathological hypertrophy (14), but some studies resulted in discrepant results (15). To further understand the role of Cn in the development and normal physiological process in the heart, several groups of investigators generated knockout (KO) animals of specific Cn subunits (2, 16). In mammals, catalytic subunit A is encoded by three genes, and regulatory subunit B is encoded by two genes, from which two catalytic (CnAalpha and CnAbeta) and one regulatory (CnB1) are expressed in the heart (10). Although global deletion of CnB leads to embryonic lethality (5), the cardiac-restricted deletion of CnB1, as presented by Schaeffer et al. (12) in last month's issue of the American Journal of Physiology-Heart and Circulatory Physiology, allowed vital mice to be born and further characterizes the role of Cn signaling in the heart development and its function. These mice were initially used and partially characterized in other studies by the same group of investigators (13). In the present paper, mice with cardiac-specific disruption of the gene encoding the Cn regulatory subunit B1 show that Cn is necessary for normal postnatal cardiac growth. Reduced expression of CnB1 results in reduced cardiac biventricular-to-body weight ratios, systolic and diastolic dysfunction, plus increased mortality reaching 100% by 7 mo of age. Interestingly, the dramatic alterations in cardiac function observed at 3 mo of age using both echocar-diography and hemodynamic measurements were not accompanied by any histological abnormalities in cardiac myocytes, such as myofibrillar disarray and fibrosis. However, at this time point, the atria showed significant fibrosis and thrombosis, most likely as a result of decreased compliance of ventricles and increased atrial pressure. Moreover, such significant changes in cardiac dynamics were not explained by any significant changes in metabolism, since only mild impairment of fatty acid oxidation in mitochondria isolated from the ventricles was found (12).