In cardiomyocytes, mechanical stress induces a variety of hypertrophic responses including an increase in protein synthesis and a reprogramming of gene expression. Recently, the calcium signaling has been reported to play an important role in the development of cardiac hypertrophy. In this article, we report on the role of the calcium signaling in stretch-induced gene expression in cardiomyocytes. Stretching of cultured cardiomyocytes up-regulates the expression of brain natriuretic peptide (BNP). Intracellular calcium-elevating agents such as the calcium ionophore A23187, the calcium channel agonist BayK8644 and the sarcoplasmic reticulum calcium-ATPase inhibitor thapsigargin up-regulate BNP gene expression. Conversely, stretch-induced BNP gene expression is suppressed by EGTA, stretch-activated ion channel inhibitors, voltage-dependent calcium channel antagonists, and long-time exposure to thapsigargin. Furthermore, stretch increases the activity of calcium-dependent effectors such as calcineurin and calmodulin-dependent kinase II, and inhibitors of calcineurin and calmodulin-dependent kinase II significantly attenuated stretch-induced hypertrophy and BNP expression. These results suggest that calcineurin and calmodulin-dependent kinase II are activated by calcium influx and subsequent calcium-induced calcium release, and play an important role in stretch-induced gene expression during the development of cardiac hypertrophy.
"Follow-up functional studies show that neonatal rat cardiomyocytes express a very low level of CaSR, yet cinacalcet does affect the expression of BNP mRNA significantly at either 1 or 2 mmol/L Ca. Although it cannot be ruled out that the low level of CaSR expression in cardiomyocytes is responsible for cinacalcet's effect on BNP mRNA expression, the interaction between cinacalcet and the other proteins can also lead to its effect on BNP expression as reported previously that some of these proteins are involved in regulating BNP expression (Lubic et al. 1995; Kudoh et al. 2003; Hall 2005). BNP is known to be associated with LVH (Cosson 2004; Ritchie et al. 2009), a common condition in CKD, which often leads to heart failure (Bluemke et al. 2008) and increased risks of hospitalization and mortality (Gwadry-Sridhar et al. 2004; Sciacqua et al. 2006; Pons et al. 2010). "
[Show abstract][Hide abstract] ABSTRACT: This study investigates the time-dependent effects of cinacalcet on serum calcium, phosphorus, and parathyroid hormone (PTH) levels in 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency. In this study, 5/6 NX male, Sprague-Dawley rats were treated with vehicle or cinacalcet (10 mg/kg, oral, 1× daily). On Day 0 (before treatment), Day 12 and 13 after treatment (to approximate the clinical practice), and also at 0, 1, 4, 8, 16, and 24 hours after the last dosing, blood was collected for analysis. After 12 or 13 days of cinacalcet treatment, modest changes were observed in serum Ca and phosphorus (Pi), while PTH decreased by >45% to Sham levels (152 ± 15 pg/mL). Detailed mapping found that cinacalcet caused a significant time-dependent decrease in serum Ca following dosing, reaching a lowest point at 8 hours (decrease by 20% to 8.43 ± 0.37 mg/dL), and then returning to normal at 24 hours. Cinacalcet also caused a significant increase in serum Pi levels (by 18%). To investigate the potential mechanism of action, a broad approach was taken by testing cinacalcet in a panel of 77 protein-binding assays. Cinacalcet interacted with several channels, transporters, and neurotransmitter receptors, some of which are involved in brain and heart, and may impact Ca homeostasis. Cinacalcet dose-dependently increased brain natriuretic peptide (BNP) mRNA expression by 48% in cardiomyocytes, but had no significant effects on left ventricular hypertrophy and cardiac function. The results suggest that cinacalcet's hypocalcemic effect may be due to its nonspecific interaction with other receptors in brain and heart.
"Its physiologic effects antagonise those of angiotensin II and, since there is a strong relationship between plasma BNP concentration and impaired ventricular function , BNP assays are currently used to monitor cardiac decompensation. The cellular mechanisms which control secretion of this peptide are as yet poorly understood, although it seems that changes in intracellular calcium concentration affect BNP gene expression in ventricular hypertrophy . "
[Show abstract][Hide abstract] ABSTRACT: The cellular mechanisms that regulate B-type natriuretic secretion are not well elicited. Intracellular fluctuation of calcium ions rate seems to be implicated.
In this study, we evaluate the role of ventricular transmembrane calcium channels in the secretion of BNP in normal adult rats (group N) and pressure overload hypertrophied ones (group H).
We measured plasma BNP concentration and BNP concentration in culture media of cardiomyocytes from N and H group in the presence and absence of calcium channels antagonists.
Plasma BNP concentration was increased in H group in comparison to N group (0.630+/-0.008 ng/ml versus 0.106+/-0.004 ng/ml; p<0.01). This increase in BNP level was also obtained in culture media of H group in comparison to N group (3.45+/-0.7 ng/ml versus 0.53+/-0.22 ng/ml). However, the presence of calcium channels antagonists in the culture media of cardiomyocytes had decreased BNP concentration in both N (nifedipine: 0.22+/-0.04 ng/ml; verapamil: 0.19+/-0.05 ng/ml; diltiazem: 0.17+/-0.03 ng/ml; p<0.05) and H group (nifedipine: 0.18+/-0.05 ng/ml; verapamil: 0.23+/-0.04 ng/ml; diltiazem: 0.28+/-0.1 ng/ml; p<0.05).
These results suggest that transmembrane calcium channels may have an important role in the regulation of BNP secretion.
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