scholarly journals Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment

2019 ◽  
Vol 11 (513) ◽  
pp. eaaw6419 ◽  
Author(s):  
Honghai Liu ◽  
Cheng-Hai Zhang ◽  
Niyatie Ammanamanchi ◽  
Sangita Suresh ◽  
Christopher Lewarchik ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptors ◽  
Transcriptional Profiling ◽  
Pulmonary Stenosis ◽  
Underlying Mechanism ◽  
The United States ◽  
Heart Tissue ◽  
Developing Heart ◽  
Β Adrenergic Receptors

One million patients with congenital heart disease (CHD) live in the United States. They have a lifelong risk of developing heart failure. Current concepts do not sufficiently address mechanisms of heart failure development specifically for these patients. Here, analysis of heart tissue from an infant with tetralogy of Fallot with pulmonary stenosis (ToF/PS) labeled with isotope-tagged thymidine demonstrated that cardiomyocyte cytokinesis failure is increased in this common form of CHD. We used single-cell transcriptional profiling to discover that the underlying mechanism of cytokinesis failure is repression of the cytokinesis gene ECT2, downstream of β-adrenergic receptors (β-ARs). Inactivation of the β-AR genes and administration of the β-blocker propranolol increased cardiomyocyte division in neonatal mice, which increased the number of cardiomyocytes (endowment) and conferred benefit after myocardial infarction in adults. Propranolol enabled the division of ToF/PS cardiomyocytes in vitro. These results suggest that β-blockers could be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.

scholarly journals Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment

2019 ◽  
Author(s):  
Honghai Liu ◽  
Cheng-Hai Zhang ◽  
Niyatie Ammanamanchi ◽  
Sangita Suresh ◽  
Christopher Lewarchik ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptors ◽  
Transcriptional Profiling ◽  
Pulmonary Stenosis ◽  
Underlying Mechanism ◽  
Developing Heart ◽  
The Us ◽  
Β Blocker ◽  
Β Blockers ◽  
Β Adrenergic Receptors

ABSTRACT/SUMMARYOne million patients with congenital heart disease (CHD) live in the US. They have a lifelong risk of developing heart failure. Current concepts do not sufficiently address mechanisms of heart failure development specifically for these patients. We show that cardiomyocyte cytokinesis failure is increased in tetralogy of Fallot with pulmonary stenosis (ToF/PS), a common form of CHD. Labeling of a ToF/PS baby with isotope-tagged thymidine showed cytokinesis failure after birth. We used single-cell transcriptional profiling to discover that the underlying mechanism is repression of the cytokinesis gene ECT2, and show that this is downstream of β-adrenergic receptors (β-AR). Inactivation of the β-AR genes and administration of the β-blocker propranolol increased cardiomyocyte division in neonatal mice, which increased the endowment and conferred benefit after myocardial infarction in adults. Propranolol enabled the division of ToF/PS cardiomyocytes. These results suggest that β-blockers should be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.

Abstract 15295: Molecular Mechanism of Chronic Sildenafil-Caused Regression of Heart Failure: Effects on the Express of Cardiac SR Ca2+-ATPase, Subtype of β-Adrenergic Receptors and Nitric Oxide Synthase Isoforms

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Heng-Jie Cheng ◽  
Tiankai Li ◽  
Che Ping Cheng
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Adrenergic Receptors ◽  
Left Ventricular ◽  
Male Rats ◽  
Protein Levels ◽  
Myocyte Function ◽  
Oxide Synthase ◽  
Β Adrenergic Receptors

Background: Sildenafil (SIL), a selective inhibitor of PDE5 has been shown to exert profound beneficial effects in heart failure (HF). Recently we further found that SIL caused regression of cardiac dysfunction in a rat model with isoproterenol (ISO)-induced progressive HF. However, the molecular basis is unclear. We hypothesized that reversal of HF-induced detrimental alterations on the expressions of cardiac SR Ca 2+ -ATPase (SERCA2a), β-adrenergic receptors (AR) and nitric oxide synthase (NOS) isoforms by SIL may play a key role for its salutary role in HF. Methods: Left ventricular (LV) and myocyte function and the protein levels of myocyte β 1 - and β 3 - AR, SERCA2a, phospholamban (PLB) and three NOS were simultaneously evaluated in 3 groups of male rats (6/group): HF , 3 months (M) after receiving ISO (170 mg/kg sq for 2 days); HF/SIL , 2 M after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and Controls (C). Results: Compared with controls, ISO-treated rats progressed to severe HF at 3 M after ISO followed by significantly decreased LV contractility (E ES , HF: 0.7 vs C: 1.2 mmHg/μl) and slowed LV relaxation, reductions in the peak velocity of myocyte shortening (77 vs 136 μm/sec), relengthening (62 vs 104 μm/sec) and [Ca 2+ ] iT (0.15 vs 0.24) accompanied by a diminished myocyte inotropic response to β-AR agonist, ISO (10 -8 M). These abnormalities were associated with concomitant significant decreases in myocyte protein levels of β 1 -AR (0.23 vs 0.64), SERCA2a (0.46 vs 0.80), PLB Ser16 /PLB ratio (0.24 vs 0.40) and eNOS (0.28 vs 0.46), but significantly increases in protein levels of β 3 -AR (0.29 vs 0.10) and iNOS (0.18 vs 0.08) with relatively unchanged nNOS. Chronic SIL prevented the HF-induced decreases in LV and myocyte contraction, relaxation, peak [Ca 2+ ] iT , and restored normal myocyte contractile response to ISO stimulation. With SIL, protein levels of myocyte β 1 - and β 3 -AR, SERCA2a were restored close to control values, but eNOS was significantly elevated than controls (0.77). Conclusions: Chronic SIL prevents HF-caused downregulation of cardiac β 1 -AR and reverse contrast changes between iNOS and β 3 -AR with SERCA 2a and eNOS expression, leading to the preservation of LV and myocyte function, [Ca 2+ ] iT , and β-adrenergic reserve.

β-Adrenergic receptors, voltage-operated Ca 2+-channels, nuclear triiodothyronine receptors and triiodothyronine concentration in pig myocardium after long-term low-dose amiodarone treatment

1993 ◽  
Vol 129 (4) ◽  
pp. 337-347 ◽  
Author(s):  
Liv Bjørn-Hansen Gøtzsche
Keyword(s):  
Cardiac Surgery ◽  
Nuclear Receptors ◽  
Adrenergic Receptors ◽  
Low Dose ◽  
Binding Capacity ◽  
Drug Concentrations ◽  
Cardiac Strain ◽  
Amiodarone Treatment ◽  
Β Adrenergic Receptors

Similar features during chronic amiodarone treatment and hypothyroidism suggest that amiodarone induces a state of "triiodothyronine (T3)-resistance" or "cardiac hypothyroidism", which may predispose the heart to pump failure under conditions with severe strain, such as recovery after cardiac surgery. Disagreements exist as to how amiodarone, and possibly its main metabolite desethylamiodarone, act upon the various receptor systems in the heart. The aim of the present study was to elucidate whether chronic amiodarone treatment leads to a functional reduction in the number of myocardial nuclear T3 receptors, the myocardial tissue T3 concentration and the number of β-receptors and voltage-operated Ca2+-channels. Finally, special attention was drawn to any changes that could contribute to explain previous reports on reduced haemodynamic reserve in animals exposed to severe cardiac strain, such as cardiac surgery. Pigs (72±2 kg) were assigned randomly to amiodarone treatment (20 mg·kg−1·day−1 for 30±1 days, N = 8); controls received no medical treatment (N = 6). The left ventricle was evaluated for β-adrenergic receptors, voltage-operated Ca2+-channels, T3 nuclear receptors and tissue T3 concentration. Maximum binding capacity for β-receptors and Ca2+-channels was reduced in amiodarone-treated pigs (by 38%, p<0.05, and by 52%, p<0.01) and correlated with tissue drug concentrations for both receptor types (p<0.05). No changes were observed concerning nuclear T3 receptors. In vitro competition studies revealed that amiodarone, but not desethylamiodarone, possessed binding properties to Ca2+-channels, whereas neither of the compounds bound to β-receptors. Desethylamiodarone, but not amiodarone, competitively inhibited T3 binding to its nuclear receptors. Myocardial T3 was undetectable (<0.05 nmol/kg wet wt) in amiodarone-treated pigs. From our observations we suggest that the active metabolite desethylamiodarone, rather than the parent drug, is mainly responsible for the observed local hypothyroid-like effects during amiodarone treatment. The observed changes after treatment with low-dose amiodarone in pigs are likely to have biological implications. Functionally, the changes may imply reduced cardiac reserve during conditions of extraordinary strain.

Factors involved in delaying the rise in peripheral resistance in developing heart failure

1994 ◽  
Vol 267 (1) ◽  
pp. H211-H216 ◽  
Author(s):  
K. Kiuchi ◽  
R. P. Shannon ◽  
N. Sato ◽  
M. Bigaud ◽  
C. Lajoie ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Peripheral Resistance ◽  
Left Ventricular ◽  
Right Atrial ◽  
Plasma Norepinephrine ◽  
Peripheral Vascular ◽  
Vascular Control ◽  
Developing Heart

The development of heart failure (HF) on peripheral vascular control was studied in 10 conscious dogs with measurements of cardiac output (CO) and left ventricular (LV), arterial, and right atrial pressures. At 3 wk after pacing-induced HF, CO was not decreased from 2.5 +/- 0.2 l/min, whereas LV dP/dt fell (from 2,858 +/- 71 to 1,409 +/- 69 mmHg/s) and LV end-diastolic pressure increased (from 4.8 +/- 0.4 to 27.3 +/- 1.1 mmHg) (P < 0.05). At 4–7 wk after pacing, CO was significantly decreased (to 1.6 +/- 0.1 l/min; P < 0.05), but total peripheral resistance (TPR) did not rise, despite increases in plasma norepinephrine and renin activity (P < 0.05). In the presence of ganglionic blockade, TPR was still not increased in HF. In vitro studies in isolated femoral artery segments demonstrated reduced intrinsic tone (0.028 +/- 0.007 g/mg; P < 0.05) as compared with vessels from sham-operated controls (0.124 +/- 0.023 g/mg), whereas the intracellular calcium level was not altered in HF. Thus, during the development of HF, severe contractile dysfunction precedes the fall in CO, which, in turn, precedes the rise in TPR. The delayed rise in TPR appears to involve a reduction in intrinsic peripheral vascular tone, despite neurohumoral activation.

scholarly journals Sympathetic nerve activity promotes cardiomyocyte cell-cycle arrest and binucleation

2017 ◽  
Author(s):  
Li Chen ◽  
Alexander Y. Payumo ◽  
Kentaro Hirose ◽  
Rachel B. Bigley ◽  
Jonathan Lovas ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Sympathetic Nerve ◽  
Adrenergic Receptors ◽  
Sympathetic Nerve Activity ◽  
Cardiomyocyte Proliferation ◽  
Nerve Activity ◽  
Cycle Arrest ◽  
Β Adrenergic Receptors

ABSTRACTAdult mammalian hearts typically have little capacity to regenerate after injuries such as myocardial infarction. In contrast, neonatal mice during the first week of life possess an incredible ability to regenerate their hearts, though this capacity is lost shortly after birth. The physiological triggers mediating this transition remains poorly understood. In this study, we demonstrate that sympathetic nerve activity promotes cardiomyocyte cell-cycle arrest and binucleation. In mice hearts lacking sympathetic nerve inputs, we observe increased mononucleated cardiomyocyte numbers and elevated cardiomyocyte proliferation. Additionally, increased cardiomyocyte mononucleation and proliferation are observed in mice with genetic and pharmacological inhibition of β-adrenergic receptors (βARs), which mediate sympathetic nerve signaling. Using in vitro cultures of neonatal cardiomyocytes, we demonstrate that activation of β-adrenergic receptors results in decreased cardiomyocyte proliferation that is mediated through cyclic AMP-dependent protein kinase (PKA) signaling. Taken together, these results suggest that sympathetic nerve activity may play a role in limiting the ability of mammalian hearts to regenerate by restricting cardiomyocyte proliferation and promoting cytokinesis failure leading to multinucleation.

Demonstration of β-adrenergic receptors in rat nasal glands by an in vitro autoradiographic technique

1988 ◽  
Vol 90 (1-2) ◽  
pp. 75-77 ◽  
Author(s):  
Y.J.B. van Megen ◽  
C.J.B.M. van Ratingen ◽  
A.B.M. Klaassen ◽  
J.F. Rodrigues de Miranda ◽  
C.A.M. van Ginneken ◽  
...  
Keyword(s):  
Adrenergic Receptors ◽  
Autoradiographic Technique ◽  
Β Adrenergic Receptors ◽  
Nasal Glands
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