monensin and Cardiomegaly

Cardiac hypertrophy (CH) generally occurs as the result of the sustained mechanical stress caused by elevated systemic arterial blood pressure (BP). However, in animal models, elevated salt intake is associated with CH even in the absence of significant increases in BP. We hypothesize that CH is not exclusively the consequence of mechanical stress but also of other factors associated with elevated BP such as abnormal cell sodium homeostasis. We examined the effect of small increases in intracellular sodium concentration ([Na(+)](i)) on transcription factors and genes associated with CH in a cardiac cell line. Increases in [Na(+)](i) led to a time-dependent increase in the expression levels of mRNA for natriuretic peptide and myosin heavy chain genes and also increased myocyte enhancer factor (MEF)2/nuclear factor of activated T cell (NFAT) transcriptional activity. Increases in [Na(+)](i) are associated with activation of salt-inducible kinase 1 (snflk-1, SIK1), a kinase known to be critical for cardiac development. Moreover, increases in [Na(+)](i) resulted in increased SIK1 expression. Sodium did not increase MEF2/NFAT activity or gene expression in cells expressing a SIK1 that lacked kinase activity. The mechanism by which SIK1 activated MEF2 involved phosphorylation of HDAC5. Increases in [Na(+)](i) activate SIK1 and MEF2 via a parallel increase in intracellular calcium through the reverse mode of Na(+)/Ca(2+)-exchanger and activation of CaMK1. These data obtained in a cardiac cell line suggest that increases in intracellular sodium could influence myocardial growth by controlling transcriptional activation and gene expression throughout the activation of the SIK1 network.

Topics: Biopsy; Cardiomegaly; Cell Line; Gene Expression; Heart Atria; Histone Deacetylases; Humans; Hydrogen-Ion Concentration; MADS Domain Proteins; MEF2 Transcription Factors; Monensin; Myocytes, Cardiac; Myogenic Regulatory Factors; NFATC Transcription Factors; Phosphorylation; Plasmids; Protein Serine-Threonine Kinases; RNA; Sodium; Transcription Factors; Transcription, Genetic; Transfection

1. Prolonged existence of hypertension is known to induce a compensatory increase in cardiac weight, later followed by a loss of functional responsiveness to biological stimuli. 2. It was the aim of the present study to investigate the functional responses of hypertrophied hearts to rising levels of intracellular calcium. The experiments were performed using two different degrees of cardiac hypertrophy, the first as obtained in spontaneously hypertensive rats (SHR) of 18-20 weeks old, the second by using rats, 32-34 weeks old, with a surgically induced stenosis of the thoracic aorta (ASR). The ASR, which showed signs of overt heart failure, may be presented as a model for hypertension-induced end-stage cardiac hypertrophy. Age-matched normotensive Wistar-Kyoto rats (WKY) and sham-operated Wistar rats served as respective controls. 3. Different methods were employed such as increasing the extracellular Ca2+ concentration, stimulation of calcium influx by means of the calcium entry promoter Bay K 8644, or altering the sodium-calcium exchange by means of the sodium ionophore monensin. 4. The inotropic responses induced by increasing the extracellular Ca2+ concentration or provoked by the calcium entry promoter Bay K 8644 proved more pronounced in hearts taken from SHR of 18 weeks old than in those from normotensive control rats, whereas the response to monensin was found to be the same in both types of hearts. In the hearts of ASR, however, the inotropic responses to Ca2+, Bay K 8644 and monensin were strongly impaired. 5. These data demonstrate that in functional experiments the sensitivity to Ca2+, which represents the main pathway in establishing a contraction, is strongly reduced in advanced cardiac hypertrophy.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Blood Pressure; Calcium; Cardiomegaly; Coronary Circulation; Extracellular Space; Heart; Heart Rate; Hypertension; In Vitro Techniques; Ions; Male; Monensin; Myocardial Contraction; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Sensitivity and Specificity