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

Abstract

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 Prevents Cytosolic Ca2+ Overload and Cell Hypercontracture in Cardiomyocytes

“…Although STC1 has been reported to decrease [Ca 2+ ]i in a variety of tissues, 1,5,6 the present study has revealed that it did not affect cell shortening or the Ca 2+ transients in fresh isolated cardiomyocytes. In cardiomyocytes exposed to ouabain, STC1 did not affect the amplitude of the Ca 2+ transients nor the fraction of cell shortening.…”

“…10 However, it has been recently reported that STC1 decreases the intracellular Ca 2+ concentration. 1,5,6 To evaluate the effects of STC1 on impaired cardiomyocytes, we examined whether it inhib- …”

“…1 STC1 is a glycoprotein hormone that is expressed in many organs and is believed to contribute to calcium homeostasis in the gut, heart, brain, and other organs. The fact that, although STC1 is widely distributed in tissues, circulating STC1 is undetectable, except in pregnancy, 2 is strongly suggestive of its autocrine or paracrine role.…”

“…Further, in cultured adult rat cardiomyocytes, which are used as a model of heart failure, the STC1 protein inhibits Ca 2+ influx via the L-type Ca 2+ channel and decreases intracellular calcium ([Ca 2+ ]i). 1 However, the localization of the STC1 receptor in the cardiomyocyte is still unclear.…”

Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport

“…The occurrence of STC is not restricted to fish; it is found in all vertebrates studied so far. Recently, STC was found to inhibit L-type calcium channels in human cardiomyocytes (44).…”