Stanniocalcin-1 is a naturally occurring L-channel inhibitor in cardiomyocytes: relevance to human heart failure

Cardiomyocytes of the failing heart undergo profound phenotypic and structural changes that are accompanied by variations in the genetic program and profile of calcium homeostatic proteins. The underlying mechanisms for these changes remain unclear. Because the mammalian counterpart of the fish calcium-regulating hormone stanniocalcin-1 (STC1) is expressed in the heart, we reasoned that STC1 might play a role in the adaptive-maladaptive processes that lead to the heart failure phenotype. We examined the expression and localization of STC1 in cardiac tissue of patients with advanced heart failure before and after mechanical unloading using a left ventricular assist device (LVAD), and we compared the results with those of normal heart tissue. STC1 protein is markedly upregulated in cardiomyocytes and arterial walls of failing hearts pre-LVAD and is strikingly reduced after LVAD treatment. STC1 is diffusely expressed in cardiomyocytes, although nuclear predominance is apparent. Addition of recombinant STC1 to the medium of cultured rat cardiomyocytes slows their endogenous beating rate and diminishes the rise in intracellular calcium with each contraction. Furthermore, using whole cell patch-clamp studies in cultured rat cardiomyocytes, we find that addition of STC1 to the bath causes reversible inhibition of transmembrane calcium currents through L-channels. Our data suggest differential regulation of myocardial STC1 protein expression in heart failure. In addition, STC1 may regulate calcium currents in cardiomyocytes and may contribute to the alterations in calcium homeostasis of the failing heart.

stanniocalcin-1 (STC1) is a homodimeric glycoprotein hormone involved in calcium regulation in bony fish (8), where elevation of serum calcium triggers the release of STC1 from the corpuscles of Stannius (23), organs associated with the kidneys (26). On circulation in the gill and intestine, STC1 inhibits calcium flux from the aquatic environment through these organs, thus maintaining normal calcium concentrations in the blood (15, 24). In mammals, STC1 is expressed in multiple organs, including the heart, skeletal muscle, brain, thyroid, spleen, thymus, parathyroid, lung, kidney, pancreas, small intestine, colon, placenta, ovary, testes, and prostate (4, 5, 22). The wide expression of STC1 suggested that it might function in an autocrine and/or paracrine manner, whereas its localization to the heart and skeletal muscle suggested a role in myocyte function.

Through the evolutionary process from fish to mammals, STC1 appears to have maintained its functional role in calcium regulation, because mammalian STC1 appears to be involved in calcium homeostasis in the normal physiology of the gut (16) and in the adaptive response of brain cells to ischemic injury (28). Because cardiomyocyte calcium homeostasis demonstrates a wide range of abnormalities in patients with heart failure (2, 9, 11, 13, 17, 21), we hypothesized that myocardial expression of STC1 may be relevant to calcium homeostasis in the failing heart.

Our current data suggest differential expression of STC1 protein in cardiomyocytes and blood vessel walls of failing hearts and are consistent with a potential role for STC1 in cardiomyocyte calcium homeostasis.