المؤلفون: Kai C. Wollert, Michelle A. Sargent, Hanna Osinska, Jeffery D. Molkentin, Jeffrey Robbins, Joerg Heineke, Allen J. York

المصدر: Journal of Molecular and Cellular Cardiology. 48:1080-1087

مصطلحات موضوعية: Cardiomyopathy, Dilated, medicine.medical_specialty, Programmed cell death, Necrosis, Cardiomyopathy, Mice, Transgenic, Biology, Models, Biological, complex mixtures, Article, Mice, Internal medicine, medicine, Animals, cardiovascular diseases, Molecular Biology, Mice, Knockout, Cell Death, Calcineurin, Myocardium, Heart, Dilated cardiomyopathy, musculoskeletal system, medicine.disease, Cardiovascular physiology, Transplantation, Disease Models, Animal, Endocrinology, Gene Expression Regulation, Echocardiography, cardiovascular system, Calcium, Myocardial fibrosis, medicine.symptom, Cardiology and Cardiovascular Medicine

الوصف: Dilated cardiomyopathy (DCM) is a relatively common disease with a poor prognosis. Given that the only meaningful treatment for DCM is cardiac transplantation, investigators have explored the underlying molecular mechanisms of this disease in the hopes of identifying novel therapeutic targets. One such target is the serine-threonine phosphatase calcineurin, a Ca2+-activated signaling factor that is known to regulate the cardiac hypertrophic program, although its role in DCM is currently unknown. In order to address this issue, we crossed muscle lim protein (MLP) knock-out mice-a murine model of DCM-with calcineurin A beta ko mice, which lack the stress responsive isoform of calcineurin that critically regulates the cardiac hypertrophic response. Interestingly, the majority (73%) of the MLP/calcineurin A beta double knock-out mice died within 20 days of birth with signs of cardiomyopathy. Ultrastructural examination revealed enhanced cardiomyocyte apoptosis and necrosis in the postnatal myocardium of these mice. The MLP/calcineurin A beta double knock-out mice that survived until adulthood showed reduced left ventricular function, enhanced apoptotic and necrotic cardiomyocyte death and augmented myocardial fibrosis compared to various control groups. Antithetically, mild overexpression of activated calcineurin in the mouse heart improved function and adverse remodeling in MLP knock-out mice. Collectively, these results reveal an important and previously unrecognized protective function of endogenous myocardial calcineurin in a mouse model of dilated cardiomyopathy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::03a8528d994006920245a5d0532d11b4Test
https://doi.org/10.1016/j.yjmcc.2009.10.012Test

المؤلفون: Jason R. Waggoner, Evangelia G. Kranias, Jeffrey Robbins, Kobra Haghighi, Kenneth S. Ginsburg, Bryan Mitton, Donald M. Bers

المصدر: American Journal of Physiology-Heart and Circulatory Physiology. 296:H698-H703

مصطلحات موضوعية: medicine.medical_specialty, SERCA, Physiology, Heart Ventricles, Genetic Vectors, Biology, Sodium-Calcium Exchanger, Adenoviridae, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Contractility, Mice, Transduction, Genetic, Caffeine, Physiology (medical), Calcium-binding protein, Internal medicine, medicine, Animals, Myocyte, Myocytes, Cardiac, Calcium Signaling, Phosphorylation, Cells, Cultured, Calcium signaling, Sodium-calcium exchanger, Endoplasmic reticulum, Calcium-Binding Proteins, Isoproterenol, Biological Transport, Articles, Adrenergic beta-Agonists, musculoskeletal system, Myocardial Contraction, Up-Regulation, Phospholamban, Sarcoplasmic Reticulum, Endocrinology, cardiovascular system, Calcium, Rabbits, Cardiology and Cardiovascular Medicine, tissues, circulatory and respiratory physiology

الوصف: Phospholamban has been suggested to be a key regulator of cardiac sarcoplasmic reticulum (SR) Ca cycling and contractility and a potential therapeutic target in restoring the depressed Ca cycling in failing hearts. Our understanding of the function of phospholamban stems primarily from studies in genetically altered mouse models. To evaluate the significance of this protein in larger mammalian species, which exhibit Ca cycling properties similar to humans, we overexpressed phospholamban in adult rabbit cardiomyocytes. Adenoviral-mediated gene transfer, at high multiplicities of infection, resulted in an insignificant 1.22-fold overexpression of phospholamban. There were no effects on twitch Ca-transient amplitude or decay under basal or isoproterenol-stimulated conditions. Furthermore, the SR Ca load and Na/Ca exchanger function were not altered. These apparent differences between phospholamban overexpression in rabbit compared with previous findings in the mouse may be due to a significantly higher (1.5-fold) endogenous phospholamban-to-sarco(endo)plasmic reticulum Ca-ATPase (SERCA) 2a ratio and potential functional saturation of SERCA2a by phospholamban in rabbit cardiomyocytes. The findings suggest that important species-dependent differences in phospholamban regulation of SERCA2a occur. In larger mammals, a higher fraction of SERCA2a pumps are regulated by phospholamban, and this may influence therapeutic strategies to enhance cardiac contractility and functional cardiac reserve.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d9664d304d561cf3f4954b779da8dd89Test
https://doi.org/10.1152/ajpheart.00272.2008Test

المؤلفون: Jeffrey Robbins, So ichiro Yasuda, Joseph M. Metzger, Sakthivel Sadayappan, Pierre Coutu

المصدر: Circulation research. 101(4)

مصطلحات موضوعية: Myofilament, medicine.medical_specialty, Cell Membrane Permeability, Physiology, Mice, Transgenic, macromolecular substances, Adenoviridae, Membrane Potentials, Contractility, Rats, Sprague-Dawley, Mice, Internal medicine, Isometric Contraction, Troponin I, medicine, Myocyte, Animals, Myocytes, Cardiac, cardiovascular diseases, Cells, Cultured, biology, Chemistry, Genetic transfer, Cardiac myocyte, Calcium-Binding Proteins, Molecular Mimicry, Gene Transfer Techniques, musculoskeletal system, Troponin, Myocardial Contraction, Phospholamban, Rats, Endocrinology, cardiovascular system, biology.protein, Calcium, Cardiology and Cardiovascular Medicine

الوصف: Elucidating the relative roles of cardiac troponin I (cTnI) and phospholamban (PLN) in β-adrenergic–mediated hastening of cardiac relaxation has been challenging and controversial. To test the hypothesis that β-adrenergic phosphorylation of cTnI has a prominent role in accelerating cardiac myocyte relaxation performance we used transgenic (Tg) mice bearing near complete replacement of native cTnI with a β-adrenergic phospho-mimetic of cTnI whereby tandem serine codons 23/24 were converted to aspartic acids (cTnI S23/24D). Adult cardiac myocytes were isolated and contractility determined at physiological temperature under unloaded and loaded conditions using micro-carbon fibers. At baseline, cTnI S23/24D myocytes had significantly faster relaxation times relative to controls, and isoproterenol stimulation (Iso) had only a small effect to further speed relaxation in cTnI S23/24D myocytes (delta Iso: 7.2 ms) relative to the maximum Iso effect (31.2 ms) in control. The Ca 2+ transient decay rate was similarly accelerated by Iso in Tg and nontransgenic (Ntg) myocytes. Gene transfer of cTnI S23/24D to myocytes in primary culture showed comparable findings. Gene transfer of cTnI with both serines 23/24 converted to alanines (cTnI S23/24A), or gene transfer of slow skeletal TnI, both of which lack PKA phosphorylation sites, significantly blunted Iso-mediated enhanced relaxation compared with controls. Gene transfer of wild-type cTnI had no effect on relaxation. These findings support a key role of cTnI in myocyte relaxation and highlight a direct contribution of the myofilaments in modulating the dynamics of myocardial performance.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::97675e65f0002fba5afebd6843522582Test
https://pubmed.ncbi.nlm.nih.gov/17702976Test

المؤلفون: Rosalvo T. H. Fogaça, Beata M. Wolska, Grace M. Arteaga, James R. Peña, Fernando Augusto Lavezzo Dias, Lori A. Walker, Kalpana Vijayan, John S. Walker, Yunbo Ke, Atsushi Sanbe, Jeffrey Robbins

المصدر: Journal of molecular and cellular cardiology. 41(2)

مصطلحات موضوعية: Genetically modified mouse, Cardiac function curve, medicine.medical_specialty, Myosin Light Chains, Stimulation, Blood Pressure, Mice, Transgenic, macromolecular substances, Biology, Contractility, Mice, Internal medicine, Myosin, medicine, Myocyte, Animals, Myocytes, Cardiac, Phosphorylation, Molecular Biology, Myosin-Light-Chain Kinase, Myocardium, Cardiac muscle, musculoskeletal system, Myocardial Contraction, medicine.anatomical_structure, Endocrinology, Calcium, Cardiology and Cardiovascular Medicine, Protein Processing, Post-Translational

الوصف: Although it has been suggested that in cardiac muscle the phosphorylation level of myosin regulatory light chain (RLC) correlates with frequency of stimulation, its significance in the modulation of the force-frequency and pressure-frequency relationships remains unclear. We examined the role of RLC phosphorylation on the force-frequency relation (papillary muscles), the pressure-frequency relation (Langendorff perfused hearts) and shortening-frequency relation (isolated cardiac myocytes) in nontransgenic (NTG) and transgenic mouse hearts expressing a nonphosphorylatable RLC protein (RLC(P-)). At 22 degrees C, NTG and RLC(P-) muscles showed a negative force-frequency relation. At 32 degrees C, at frequencies above 1 Hz, both groups showed a flat force-frequency relation. There was a small increase in RLC phosphorylation in NTG muscles when the frequency of stimulation was increased from 0.2 Hz to 4.0 Hz. However, the level of RLC phosphorylation in these isolated muscles was significantly lower compared to samples taken from NTG intact hearts. In perfused hearts, there was no difference in the slope of pressure-frequency relationship between groups, but the RLC(P-) group consistently developed a reduced systolic pressure and demonstrated a decreased contractility. There was no difference in the level of RLC phosphorylation in hearts paced at 300 and 600 bpm. In RLC(P-) hearts, the level of TnI phosphorylation was reduced compared to NTG. There was no change in the expression of PLB between groups, but expression of SERCA2 was increased in hearts from RLC(P-) compared to NTG. In isolated cardiac myocytes, there was no change in shortening-frequency relationship between groups. Moreover, there was no change in Ca(2+) transient parameters in cells from NTG and RLC(P-) hearts. Our data demonstrate that in cardiac muscle RLC phosphorylation is not an essential determinant of force- and pressure-frequency relations but the absence of RLC phosphorylation decreases contractility in force/pressure developing preparations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::96457104669cfae488f74b73a6f29b9cTest
https://pubmed.ncbi.nlm.nih.gov/16806259Test