Furthermore, many studies indicate that sustained cardiac hypertrophy is closely associated with reduced contractility and an increased risk of heart failure Transgenic mice that lack a hypertrophic response mechanism suffer less cardiac dysfunction than normal mice when facing long-term mechanical stress In light of this evidence, a new paradigm has emerged in which it is argued that the signaling pathways stimulated during the hypertrophic process may actually play a greater role in the pathogenesis of heart failure than the original stress on the heart.
According to this model, heightened stimulation by the sympathetic nervous system elicits a hypertrophic response in the heart that is initially beneficial but becomes maladaptive when sustained. Over the last decade and a half, cardiovascular research has been revolutionized through the use of genetically engineered mouse models. Mouse lines have been developed to model every aspect of cardiac pathology. PI3K, which belongs to a conserved family of lipid kinases that are involved in the regulation of a variety of cellular functions including cell growth, survival, signal transduction and apoptosis, is activated in cardiac myocytes during the hypertrophic response PI3K, via its lipid kinase activity, catalyzes the production of D-3 phosphoinositides, which recruit adaptor proteins essential to receptor internalization.
Recently, we demonstrated that internalization of the receptor also requires the protein kinase activity of PI3K involving tropomyosin phosphorylation Further investigation of the secondary signaling pathways these molecules are involved in, is needed to fully understand how best to target these molecules for the treatment of CHF. I am grateful to Drs. Aleksandr Vendrov at University of North Carolina, Chapel Hill, for their encouragement and critical reading of the manuscript. National Center for Biotechnology Information , U. Journal List Mcgill J Med v.
Mcgill J Med. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Open in a separate window. Figure 1. Figure 2.
Heart and stroke statistical update. Dallas, Tx: American Heart Association; Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Koch WJ. Genetic and phenotypic targeting of beta-adrenergic signaling in heart failure. Molecular and Cellular Biochemistry. The G protein-coupled receptor repertoires of human and mouse. Wess J. G-protein-coupled receptors:molecular mechanisms involved in receptor activation and selectivity of G-protein recognition.
Xiao RP. Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G s and G i proteins. Sci STKE. Catecholamines, sympathetic drugs, and adrenergic receptor anatagonists. In: Hardman J, Limbird L, editors. The pharmacological basis of therapeutics. New York: McGraw-Hill; Anti-beta 1 -adrenergic receptor antibodies and heart failure: causation, not just correlation. J Clin Invest. Pavoine C, Defer N. The cardiac beta2-adrenergic: signaling a new role for the cPLA2.
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However, they were euthanized when they reached a moribund state. Braun, Melsungen, Germany under isoflurane anaesthesia. Braun, Melsungen, Germany and left ventricles were isolated followed by flash freezing in liquid nitrogen. Samples were dissolved in the accordant buffer and measurements were performed according to instruction of the manufacturer. Resulting values of cAMP concentration were corrected for dilution effects. These animals were not included in interventions or other investigations. Mice were euthanized using humane endpoints to prevent unnecessary suffering when they were moribund.
Repeated ECGs and echocardiograms were done until the age of 20 months to detect age-related alterations of cardiac phenotype. After death, organs were excised and subjected to further analyses. For detecting heart rate in conscious mice, gel-coated ECG electrodes were fixed at the animals paws and the animal was brought in a measuring construction where it was not able to disconnect itself.
Only data from continuous recordings of 20—30 ECG signals were used in the analyses.
Transthoracic echocardiography was performed as previously described in detail [ 17 ]. The heart was imaged using the two-dimensional mode in the parasternal short-axis view, including papillary muscles, to position the M-mode cursor perpendicular to the ventricular septum and LV posterior wall. M-mode measurements of left ventricular dimensions were averaged from at least three cycles, using the leading edge—to—leading edge convention adopted by the American Society of Echocardiography. The investigator who conducted the echocardiography was blinded for the treatment status.
Mice were placed on a heating pad and mechanically ventilated. The right internal carotid artery was exposed, and a microtip catheter transducer SPR, Millar Instruments, Houston, Tex, USA was inserted into the right carotid artery and advanced into the left ventricle under pressure control.
- Signal Transduction and Cardiac Hypertrophy;
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The raw conductance volumes were corrected for parallel conductance by the hypertonic saline dilution method. For absolute volume measurements, the catheter was calibrated with known volumes of heparin-treated mouse blood. This was carried out in an additional experimental setup to avoid the influence of volume overload. Organs such as heart, lung and liver were excised, weighed, and frozen in liquid nitrogen. The heart was divided into the atria, left ventricle including the intraventricular septum, and the right ventricle. Histological studies were conducted using formalin-fixed, paraffin embedded hearts from animals of all groups.
Additionally, picrosirius red staining was done to detect collagen deposition. Collagen area fraction in percent was then calculated as collagen area to tissue area ratio.
Signal Transduction and Cardiac Hypertrophy
Protein lysates were prepared from the left ventricles of WT and transgenic mice 3 months unless otherwise stated. Protein concentration was measured using BCA protein assay Interchim. GAPDH was used as an internal control. Protein bands were subsequently detected with enhanced chemiluminescence and sections were exposed to X-ray film.
A standard curve was run with the dilution series of the amplified fragment allowing for mRNA copy number calculation.
Signal Transduction and Cardiac Hypertrophy | SpringerLink
Mice were anesthetized with isoflurane, and Alzet osmotic minipumps model , Durect Corp, Cupertino, CA were implanted subcutaneously in the neck. Isoproterenol treatment was continued for 14 days. Differences between groups were tested for statistical significance using two-tailed Student t-test or multiple analysis of variance, when applicable, with Bonferroni post-hoc tests. SPSS V Error bars in figures indicate standard error if not indicated otherwise.
ECGs showed no other abnormalities in transgenic animals, especially atrioventricular conduction delay or the occurrence of bundle branch blocks were not increased Fig 6. Regarding gross morphological parameters of hypertrophy such as heart to body weight ratio, LV to body weight ratio and also cardiomyocyte size, no significant differences were found Table 1. Organ weights revealed no signs for cardiac decompensation as well. Also regarding cardiac fibrosis, there were no significant differences in the extent of collagen deposition in wild type and transgenic animals 3.
Apart from this there were no significant differences in echocardiographic values, especially not for end-diastolic diameter EDD or ejection fraction EF between both groups Table 2. No differences were found regarding other pressure-volume parameters. Hemodynamic data at baseline are shown in Table 3.
Echocardiographic data at the age of 20 months is shown in Table 4. Tissue samples of left ventricle after natural death showed no significant differences in the extent of collagen deposition in wild type and transgenic animals 5.
No differences in cause of death were observed between transgenic and wild type animals, especially not for the incidence of neoplasm or for pleural and pericardial effusion. Figs 10 and These alterations were associated with lower steady-state intracellular cAMP levels as compared to WT animals.
However, this murine model developed cardiomyopathy at older age, characterized by left ventricular LV dilatation and hypertrophy, reduced LV function, fibrosis, apoptosis, and shows an increased mortality [ 18 — 21 ]. Hypertension, 35 , pp.
Phosphorylation of GATA-4 is involved in alpha 1-adrenergic agonist-responsive transcription of the endothelin-1 gene in cardiac myocytes.. J Biol Chem, , pp. J Mol Biol, , pp. Combinatorial expression of GATA4, Nkx, and serum response factor directs early cardiac gene activity.. M Medline. J Physiol, , pp. Cell contpapel by membrane-cytoskeleton adhesion.. Nat Rev Mol Cell Biol, 2 , pp. Circ Res, 78 , pp. Circ Res, 75 , pp. Circ Res, 88 , pp.