Stretch-modulation of second messengers: effects on cardiomyocyte ion transport.
ABSTRACT 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.
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ABSTRACT: This review presents recent data on the structure, synthesis, and secretion of cardiac natriuretic peptides. It is known that these hormones have a broad spectrum of activity, but they remain the least studied and poorly understood link in the regulation of the water-salt homeostasis. Emphasis is placed on the problem of ontogenetic formation of the heart secretory activity during embryogenesis. We discuss the available scarce and scattered information on the paracrine and autocrine effects of the peptides on intercellular interactions, and on the division, growth and differentiation of the heart cells. These issues are hardly addressed in Russian literature.Ontogenez 01/2012; 43(3):217-28.
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ABSTRACT: BACKGROUND: Nebulette (NEBL) is a sarcomeric Z-disc protein involved in mechanosensing and force generation via its interaction with actin and tropomyosin-troponin complex. Genetic abnormalities in NEBL lead to dilated cardiomyopathy (DCM) in humans and animal models. OBJECTIVES: To determine the earliest preclinical mechanical changes in the myocardium and define underlying molecular mechanisms by which NEBL mutations lead to cardiac dysfunction. METHODS AND RESULTS: We examined cardiac function in 3-month-old non-transgenic (non-Tg) and transgenic (Tg) mice (WT-Tg, G202R-Tg, A592E-Tg) by cardiac magnetic resonance (CMR) imaging. Contractility and calcium transients were measured in isolated cardiomyocytes. A592E-Tg mice exhibited enhanced in vivo twist and untwisting rate compared to control groups. Ex vivo analysis of A592E-Tg cardiomyocytes showed blunted calcium decay response to isoproterenol. CMR imaging of G202R-Tg mice demonstrated reduced torsion compared to non-Tg and WT-Tg, but conserved twist and untwisting rate after correcting for geometric changes.Ex vivo analysis of G202R-Tg cardiomyocytes showed elevated calcium decay at baseline and a conserved contractile response to isoproterenol stress. Protein analysis showed decreased -actinin and connexin43, increased cardiac troponin I phosphorylation at baseline in G202R-Tg, providing a molecular mechanism for enhanced ex vivo calcium decay. Ultrastructurally, G202R-Tg cardiomyocytes exhibited increased I-band and sarcomere length, desmosomal separation, and enlarged t-tubules. A592E-Tg cardiomyocytes also showed abnormal ultrastructural changes and desmin downregulation. CONCLUSION: This study showed distinct effects of NEBL mutations on sarcomere ultrastructure, cellular contractile function, and calcium homeostasis in preclinical DCM in vivo. We suggest that these abnormalities correlate with detectable myocardial wall motion patterns. (Word count: 250).Journal of Molecular and Cellular Cardiology 04/2013; · 5.15 Impact Factor