scholarly journals Impaired beta-adrenergic response and decreased L-type calcium current of hypertrophied left ventricular myocytes in postinfarction heart failure

2003 ◽  
Vol 36 (5) ◽  
pp. 635-648 ◽  
Author(s):  
R.M. Saraiva ◽  
N.G.B. Chedid ◽  
C.C. Quintero H. ◽  
L.E. Díaz G. ◽  
M.O. Masuda
Keyword(s):  
Heart Failure ◽  
Calcium Current ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Beta Adrenergic ◽  
Adrenergic Response

Subcellular compartmentalization of Gs alpha in cardiac myocytes and its redistribution in heart failure

1996 ◽  
Vol 271 (6) ◽  
pp. H2209-H2217
Author(s):  
J. A. Nash ◽  
H. K. Hammond ◽  
J. E. Saffitz
Keyword(s):  
Heart Failure ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Immunogold Electron Microscopy ◽  
Beta Adrenergic ◽  
Intercalated Disks ◽  
Subcellular Compartmentalization ◽  
Gs Alpha ◽  
Heart Failure Model ◽  
Intracellular Compartmentalization

Intracellular compartmentalization of G proteins may contribute to regulating signal transduction pathways in normal and failing myocardium. To test this hypothesis, we used postembedment immunogold electron microscopy to characterize the subcellular distribution of Gs alpha in normal canine and porcine left ventricular myocytes and in myocytes from a pacing-induced heart failure model in pigs in which beta-adrenergic signaling is impaired. Gs alpha was highly compartmentalized in normal canine myocytes and was localized specifically to the sarcolemma, intercalated disks, T-tubule and sarcoplasmic reticulum (SR) triads, and myoplasm. The highest Gs alpha concentration was observed in the intercalated disks. Only 20 +/- 5% of total cellular Gs alpha was localized to the sarcolemma. The triads and myoplasm compartments contained 45 +/- 13 and 27 +/- 8% of total cellular Gs alpha, respectively. The distribution of Gs alpha in normal porcine and canine myocytes was similar. However, in failing porcine myocytes Gs alpha was redistributed from the sarcolemma and T-tubule and SR triads to the myoplasm. The proportion of total cellular Gs alpha in the sarcolemma fell from 22 +/- 5 in normal to 11 +/- 4% in failing myocytes (P < 0.005), and the proportion in T-tubule and SR triads fell from 55 +/- 5 to 40 +/- 5% (P < 0.01), with a quantitatively corresponding increase in the proportion in the myoplasm from 19 +/- 3 to 43 +/- 4% (P < 0.0001). Thus redistribution of Gs alpha from the sarcolemma and the T-tubule and SR triads, where it may transduce beta-adrenergic signals, to internal sites where such actions may be precluded, might contribute to the pathophysiology of heart failure.

Cardiac mitofusin-1 is declined in non-responding patients with idiopathic dilated cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Hsiao ◽  
I Shimizu ◽  
T Wakasugi ◽  
S Jiao ◽  
T Watanabe ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Heart Failure ◽  
Ventricular Myocytes ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Heart Failure Patients ◽  
Underlying Mechanisms ◽  
Neonatal Rat Ventricular Myocytes ◽  
Mitofusin 1

Abstract Background/Introduction Mitochondria are dynamic regulators of cellular metabolism and homeostasis. The dysfunction of mitochondria has long been considered a major contributor to aging and age-related diseases. The prognosis of severe heart failure is still unacceptably poor and it is urgent to establish new therapies for this critical condition. Some patients with heart failure do not respond to established multidisciplinary treatment and they are classified as “non-responders”. The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Purpose Studies indicate mitochondrial dysfunction has causal roles for metabolic remodeling in the failing heart, but underlying mechanisms remain to be explored. This study tried to elucidate the role of Mitofusin-1 in a failing heart. Methods We examined twenty-two heart failure patients who underwent endomyocardial biopsy of intraventricular septum. Patients were classified as non-responders when their left-ventricular (LV) ejection fraction did not show more than 10% improvement at remote phase after biopsy. Fourteen patients were classified as responders, and eight as non-responders. Electron microscopy, quantitative PCR, and immunofluorescence studies were performed to explore the biological processes or molecules involved in failure to respond. In addition to studies with cardiac tissue specific knockout mice, we also conducted functional in-vitro studies with neonatal rat ventricular myocytes. Results Twenty-two patients with IDCM who underwent endomyocardial biopsy were enrolled in this study, including 14 responders and 8 non-responders. Transmission electron microscopy (EM) showed a significant reduction in mitochondrial size in cardiomyocytes of non-responders compared to responders. Quantitative PCR revealed that transcript of mitochondrial fusion protein, Mitofusin-1, was significantly reduced in non-responders. Studies with neonatal rat ventricular myocytes (NRVMs) indicated that the beta-1 adrenergic receptor-mediated signaling pathway negatively regulates Mitofusin-1 expression. Suppression of Mitofusin-1 resulted in a significant reduction in mitochondrial respiration of NRVMs. We generated left ventricular pressure overload model with thoracic aortic constriction (TAC) in cardiac specific Mitofusin-1 knockout model (c-Mfn1 KO). Systolic function was reduced in c-Mfn1 KO mice, and EM study showed an increase in dysfunctional mitochondria in the KO group subjected to TAC. Conclusions Mitofusin-1 becomes a biomarker for non-responders with heart failure. In addition, our results suggest that therapies targeting mitochondrial dynamics and homeostasis would become next generation therapy for severe heart failure patients. Funding Acknowledgement Type of funding source: None

Troponin I phosphorylation in spontaneously hypertensive rat heart: effect of beta-adrenergic stimulation

1997 ◽  
Vol 273 (3) ◽  
pp. H1440-H1451 ◽  
Author(s):  
B. K. McConnell ◽  
C. S. Moravec ◽  
I. Morano ◽  
M. Bond
Keyword(s):  
Troponin I ◽  
Ventricular Myocytes ◽  
Spontaneously Hypertensive Rat ◽  
Left Ventricular ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
Spontaneously Hypertensive ◽  
Myosin Light Chain 2 ◽  
Wistar Kyoto ◽  
Phospholamban Phosphorylation

We compared baseline and protein kinase A (PKA)-dependent troponin I (TnI) phosphorylation in 32Pi-labeled left ventricular myocytes from hearts of 26-wk spontaneously hypertensive rats (SHR) and Wistar-Kyoto controls (WKY). TnI phosphorylation was normalized to myosin light chain 2 phosphorylation, which was invariant. There was no difference in baseline TnI phosphorylation in SHR and WKY, but stimulation with isoproterenol, norepinephrine plus prazosin, forskolin, chloroadenosine 3',5'-cyclic monophosphate, or 3-isobutyl-1-methylxanthine caused a greater increase in TnI phosphorylation in the SHR than in the WKY. This was observed both in the presence and absence of the phosphatase inhibitor calyculin A; thus the differences in TnI phosphorylation between SHR and WKY are not due to decreased phosphatase activity in the SHR. After stimulation of the beta-adrenergic pathway, phospholamban phosphorylation was not different in SHR and WKY, indicating that the observed differences may be specific for PKA phosphorylation of TnI. The increased PKA-dependent TnI phosphorylation in the SHR resulted in decreased Ca2+ sensitivity of actomyosin adenosinetriphosphatase activity as compared with the WKY. We conclude that increased PKA-dependent TnI phosphorylation in the SHR may contribute to the impaired response to sympathetic stimulation.

scholarly journals Loss of Rad-GTPase produces a novel adaptive cardiac phenotype resistant to systolic decline with aging

2015 ◽  
Vol 309 (8) ◽  
pp. H1336-H1345 ◽  
Author(s):  
Janet R. Manning ◽  
Catherine N. Withers ◽  
Bryana Levitan ◽  
Jeffrey D. Smith ◽  
Douglas A. Andres ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Output ◽  
Calcium Current ◽  
Ventricular Myocytes ◽  
Morphological Changes ◽  
Heart Function ◽  
Early Time ◽  
Cardiac Phenotype ◽  
Systolic And Diastolic Function

Rad-GTPase is a regulator of L-type calcium current (LTCC), with increased calcium current observed in Rad knockout models. While mouse models that result in elevated LTCC have been associated with heart failure, our laboratory and others observe a hypercontractile phenotype with enhanced calcium homeostasis in Rad−/−. It is currently unclear whether this observation represents an early time point in a decompensatory progression towards heart failure or whether Rad loss drives a novel phenotype with stable enhanced function. We test the hypothesis that Rad−/− drives a stable nonfailing hypercontractile phenotype in adult hearts, and we examine compensatory regulation of sarcoplasmic reticulum (SR) loading and protein changes. Heart function was measured in vivo with echocardiography. In vivo heart function was significantly improved in adult Rad−/− hearts compared with wild type. Heart wall dimensions were significantly increased, while heart size was decreased, and cardiac output was not changed. Cardiac function was maintained through 18 mo of age with no decompensation. SR releasable Ca2+ was increased in isolated Rad−/− ventricular myocytes. Higher Ca2+ load was accompanied by sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) protein elevation as determined by immunoblotting and a rightward shift in the thapsigargan inhibitor-response curve. Rad−/− promotes morphological changes accompanied by a stable increase in contractility with aging and preserved cardiac output. The Rad−/− phenotype is marked by enhanced systolic and diastolic function with increased SR uptake, which is consistent with a model that does not progress into heart failure.

Membrane-delimited stimulation of heart cell calcium current by beta-adrenergic signal-transducing Gs protein

1990 ◽  
Vol 259 (1) ◽  
pp. H264-H267 ◽  
Author(s):  
S. Pelzer ◽  
Y. M. Shuba ◽  
T. Asai ◽  
J. Codina ◽  
L. Birnbaumer ◽  
...  
Keyword(s):  
Calcium Current ◽  
Receptor Activation ◽  
Heart Cell ◽  
Ca Channels ◽  
Beta Adrenergic ◽  
Physiological Regulation ◽  
Beta Receptor ◽  
Adrenergic Response ◽  
Gs Protein ◽  
Stimulation Of

A severalfold increase in calcium current (ICa) is a signal feature of the maximal beta-adrenergic response of the heart. It is generally ascribed to enhanced adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphorylation of calcium (Ca) channels after beta-receptor activation of the guanosine nucleotide-binding (G) protein Gs, and Gs activation of the adenylyl cyclase cascade. We blocked phosphorylation pathways in guinea pig cardiomyocytes to unmask other possible ICa-stimulatory modes. In blocked cells, ICa increased by approximately 50% during 1) beta-receptor activation of Gs, 2) intracellular activation of Gs, and 3) intracellular application of preactivated Gs, We conclude that fast, membrane-delimited Gs modulation participates in the physiological regulation of cardiac ICa.

Cytosolic calcium transients in myocytes isolated from rats with ischemic heart failure

1993 ◽  
Vol 265 (6) ◽  
pp. H1953-H1964 ◽  
Author(s):  
J. M. Capasso ◽  
P. Li ◽  
P. Anversa
Keyword(s):  
Heart Failure ◽  
Mechanical Performance ◽  
Ventricular Myocytes ◽  
Diastolic Pressure ◽  
Cytosolic Calcium ◽  
Left Ventricular ◽  
Ischemic Heart ◽  
Ischemic Heart Failure ◽  
Time To Peak ◽  
Left And Right

Mechanical performance and cytosolic Ca2+ dynamics were characterized in myocytes isolated from left and right ventricles of rats with ischemic heart failure. Seven days after coronary artery narrowing (CAN) in rats filling pressures were elevated, whereas systolic pressures and ejection of blood were depressed. Left ventricular myocytes increased 18% in length and 19% in width, whereas right myocytes expanded longitudinally by 23% and transversely by 24%. Contractile behavior of myocytes displayed reductions in myocyte shortening and velocity of shortening, despite prolongation of time to peak shortening. Diastolic Ca2+ increased by 32 and 39% in left and right myocytes of CAN animals, whereas peak systolic Ca2+ in left ventricular myocytes was depressed (22%). Time to peak Ca2+ was prolonged by 68% in left myocytes. Moreover, time required for peak Ca2+ to return to diastolic levels was prolonged in left myocytes. Regression analysis revealed correlations between end-diastolic pressure and diastolic Ca2+ and peak developed pressure and systolic Ca2+. Thus ischemic heart failure finds its cellular basis in a depression in myocyte contractility that may in turn be due to alterations in cytosolic Ca2+ handling.

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