Abstract 274: Spatiotemporal Regulation of β Adrenergic Signaling In Heart failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yang K Xiang ◽  
Federica Barbagallo ◽  
Bing Xu ◽  
Qin Fu
Keyword(s):  
Heart Failure ◽  
Plasma Membrane ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Myocytes ◽  
Cardiac Disease ◽  
Spatiotemporal Regulation ◽  
Disease Therapy ◽  
Functional Implications ◽  
Underlying Mechanisms

Our long-term goal is to understand mechanisms that govern spatiotemporal regulation of cAMP/PKA signaling in cardiac myocytes under physiological and pathophysiological conditions, and their implication in cardiac disease therapy. Here we use a series of biosensors to measure cAMP/PKA activity under βAR subtype regulation. In failing cardiac myocytes, the cAMP and PKA activity are shifted from the plasma membrane to the intracellular sarcoplasmic reticulum and the myofilaments. Meanwhile, β2AR displays an increased role in signaling to the myofilaments in failing myocytes when compared to the control myocytes. Moreover, we show that an increased βAR association with phosphodiesterases promotes the alteration in spatiotemporal propagation of cAMP/PKA signaling in failing myocytes. These observations and the underlying mechanisms and functional implications will be discussed.

Astragaloside IV Inhibits Membrane Ca2+ Current but Enhances Sarcoplasmic Reticulum Ca2+ Release

2017 ◽  
Vol 45 (04) ◽  
pp. 863-877 ◽  
Author(s):  
Mei-Mi Zhao ◽  
Wen-Wen Lian ◽  
Zhuo Li ◽  
Dong-Xue Shao ◽  
Si-Chong Chen ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Sarcoplasmic Reticulum ◽  
Traditional Chinese Medicine ◽  
Cardiac Myocytes ◽  
Cardiac Disease ◽  
H9c2 Cells ◽  
Inhibitory Effects ◽  
Astragaloside Iv ◽  
Active Ingredients ◽  
Dependent Inactivation

Astragaloside IV (AS-IV) is one of the active ingredients in Astragalus membrananceus (Huangqi), a traditional Chinese medicine. The present study investigated the effects of AS-IV on Ca[Formula: see text] handling in cardiac myocytes to elucidate its possible mechanism in the treatment of cardiac disease. The results showed that AS-IV at 1 and 10[Formula: see text][Formula: see text]M reduced KCl-induced [Ca[Formula: see text]]i increase ([Formula: see text] from 1.33[Formula: see text][Formula: see text][Formula: see text]0.04 (control, [Formula: see text] 28) to 1.22[Formula: see text][Formula: see text][Formula: see text]0.02 ([Formula: see text], [Formula: see text] 29) and 1.22[Formula: see text][Formula: see text][Formula: see text]0.02 ([Formula: see text] 0.01, [Formula: see text]), but it enhanced Ca[Formula: see text] release from SR ([Formula: see text] from 1.04[Formula: see text][Formula: see text][Formula: see text]0.01 (control, [Formula: see text]) to 1.44[Formula: see text][Formula: see text][Formula: see text]0.03 ([Formula: see text], [Formula: see text]) and 1.60[Formula: see text][Formula: see text][Formula: see text]0.04 ([Formula: see text] 0.01, [Formula: see text]0), in H9c2 cells. Similar results were obtained in native cardiomyocytes. AS-IV at 1 and 10[Formula: see text][Formula: see text]M inhibited L-type Ca[Formula: see text] current ([Formula: see text] from [Formula: see text]4.42[Formula: see text][Formula: see text][Formula: see text]0.58 pA/pF of control to [Formula: see text]2.25[Formula: see text][Formula: see text][Formula: see text]0.12 pA/pF ([Formula: see text] 0.01, [Formula: see text] 5) and [Formula: see text]1.78[Formula: see text][Formula: see text][Formula: see text]0.28 pA/pF ([Formula: see text] 0.01, [Formula: see text] 5) respectively, when the interference of [Ca[Formula: see text]]i was eliminated due to the depletion of SR Ca[Formula: see text] store by thapsigargin, an inhibitor of Ca[Formula: see text] ATPase. Moreover, when BAPTA, a rapid Ca[Formula: see text] chelator, was used, CDI (Ca[Formula: see text]-dependent inactivation) of [Formula: see text] was eliminated, and the inhibitory effects of AS-IV on ICaL were significantly reduced at the same time. These results suggest that AS-IV affects Ca[Formula: see text] homeostasis through two opposite pathways: inhibition of Ca[Formula: see text] influx through L-type Ca[Formula: see text] channel, and promotion of Ca[Formula: see text] release from SR.

scholarly journals Proceedings From the 2019 Stanford Single Ventricle Scientific Summit: Advancing Science for Single Ventricle Patients: From Discovery to Clinical Applications

2020 ◽  
Vol 9 (7) ◽  
Author(s):  
Sushma Reddy ◽  
Stephanie Siehr Handler ◽  
Sean Wu ◽  
Marlene Rabinovitch ◽  
Gail Wright
Keyword(s):  
Heart Failure ◽  
Patient Outcomes ◽  
Single Ventricle ◽  
The United States ◽  
Vascular Abnormalities ◽  
The Past ◽  
Worldwide Population ◽  
Underlying Mechanisms ◽  
Fontan Patients

Abstracts Because of remarkable advances in survival over the past 40 years, the worldwide population of individuals with single ventricle heart disease living with Fontan circulation has grown to ≈70 000, with nearly half aged >18 years. Survival to at least 30 years of age is now achievable for 75% of Fontan patients. On the other hand, single ventricle patients account for the largest group of the 6000 to 8000 children hospitalized with circulation failure, with or without heart failure annually in the United States, with the highest in‐hospital mortality. Because there is little understanding of the underlying mechanisms of heart failure, arrhythmias, pulmonary and lymphatic vascular abnormalities, and other morbidities, there are no specific treatments to maintain long‐term myocardial performance or to optimize overall patient outcomes.

scholarly journals Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1617 ◽  
Author(s):  
Jin Li ◽  
Deli Zhang ◽  
Bianca J. J. M. Brundel ◽  
Marit Wiersma
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Endoplasmic Reticulum ◽  
Cardiac Disease ◽  
Healthcare Costs ◽  
Central Component ◽  
Ageing Population ◽  
Mitochondrial Stress ◽  
Underlying Mechanisms

Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function.

Crosstalk between leptin and interleukin-1β abrogates negative inotropic effects in a model of chronic hyperleptinemia

2011 ◽  
Vol 236 (11) ◽  
pp. 1263-1273 ◽  
Author(s):  
M Judith Radin ◽  
Bethany J Holycross ◽  
Sylvia A McCune ◽  
Ruth A Altschuld
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Leptin Receptor ◽  
Interleukin 1 ◽  
Negative Inotropic Effect ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Inotropic Effects ◽  
Negative Inotropic Effects

Interleukin 1 beta (IL-1 β) is a proinflammatory cytokine with potent cardiosuppressive effects. Previous studies have shown that leptin blunts the negative inotropic effects of IL-1 β in isolated adult rat cardiac myocytes. However, the interactions between leptin and IL-1 β in the heart have not been examined on a background of chronic hyperleptinemia. To study this interaction, we have chosen the SHHF rat, a model of spontaneous hypertension that ultimately develops congestive heart failure. SHHF that are heterozygous for a null mutation of the leptin receptor (+/ fa cp, HET) are phenotypically lean but chronically hyperleptinemic and develop heart failure earlier than their normoleptinemic true lean (+/+, LN) littermates. Simultaneous cell shortening and calcium transients were measured in isolated ventricular cardiac myocytes from LN and HET SHHF in response to leptin, IL-1 β or IL-1 β following one hour pretreatment with leptin. Despite evidence of metabolic leptin resistance, HET myocytes were sensitive to the negative inotropic effect of leptin, similar to LN. Contractility returned to control levels in myocytes from HET that were pretreated with leptin prior to IL-1 β, while contractility remained depressed compared with control and similar to leptin alone in LN. Chronic hyperleptinemia resulted in altered JAK/STAT signaling in response to leptin and IL-1 β in isolated perfused hearts from HET compared with LN SHHF. Phosphorylated STAT3 (pSTAT3) and STAT5 (pSTAT5) decreased when HET hearts were treated with leptin followed by IL-1 β. While decreases in pSTAT3 and pSTAT5 may be associated with abrogation of the acute negative inotropic effects of IL-1 β in the presence of leptin in HET, long-term consequences remain to be explored. This study demonstrates that the heart remains sensitive to leptin in a hyperleptinemic state. Crosstalk between leptin and IL-1 β can influence cardiac function and cytokine signaling and these interactions are moderated by the presence of long-term hyperleptinemia.

Circulating B-type natriuretic peptides in patients with acute coronary syndromes

2005 ◽  
Vol 94 (11) ◽  
pp. 926-932 ◽  
Author(s):  
Rudolf Jarai ◽  
Johann Wojta ◽  
Kurt Huber
Keyword(s):  
Heart Failure ◽  
Natriuretic Peptides ◽  
Acute Coronary Syndromes ◽  
Underlying Disease ◽  
High Risk Group ◽  
Coronary Syndromes ◽  
Short And Long Term ◽  
Underlying Mechanisms ◽  
Relationship Of

SummaryFifty percent of patients who experience death or develop heart failure after acute coronary syndromes (ACS) have extremely elevated concentrations of plasma B-type natriuretic peptides. These elevations, however, seem not to reflect permanent ventricular dysfunction or heart failure and are assumed to exist already at the onset of ischemic symptoms. The underlying mechanisms of BNP/Nt-proBNP elevations in patients withACS are still not known at present. Furthermore, the relationship of elevated BNP/Nt-proBNP with mortality but not with atherothrombotic complications of underlying disease makes it difficult to choose optimal therapeutic strategies based on plasma levels of these peptides. The remarkably high short- and long-term mortality rate associated with increases of BNP/Nt-proBNP elevations clearly show the need of further investigation to focus on this high-risk group of patients in order to clarify underlying pathomechanisms and to find optimal therapeutic approaches.

Influence of long-term treatment of imidapril on mortality, cardiac function, and gene expression in congestive heart failure due to myocardial infarction

2004 ◽  
Vol 82 (12) ◽  
pp. 1118-1127 ◽  
Author(s):  
Bin Ren ◽  
Qiming Shao ◽  
Pallab K Ganguly ◽  
Paramjit S Tappia ◽  
Nobuakira Takeda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Congestive Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Function ◽  
Term Treatment ◽  
Cardiac Performance ◽  
Long Term Treatment

Although it is generally accepted that the efficacy of imidapril, an angiotensin-converting enzyme inhibitor, in congestive heart failure (CHF) is due to improvement of hemodynamic parameters, the significance of its effect on gene expression for sarcolemma (SL) and sarcoplasmic reticulum (SR) proteins has not been fully understood. In this study, we examined the effects of long-term treatment of imidapril on mortality, cardiac function, and gene expression for SL Na+/K+ ATPase and Na+–Ca2+ exchanger as well as SR Ca2+ pump ATPase, Ca2+ release channel (ryanodine receptor), phospholamban, and calsequestrin in CHF due to myocardial infarction. Heart failure subsequent to myocardial infarction was induced by occluding the left coronary artery in rats, and treatment with imidapril (1 mg·kg–1·day–1) was started orally at the end of 3 weeks after surgery and continued for 37 weeks. The animals were assessed hemody nam ically and the heart and lung were examined morphologically. Some hearts were immediately frozen at –70 °C for the isolation of RNA as well as SL and SR membranes. The mortality of imidapril-treated animals due to heart failure was 31% whereas that of the untreated heart failure group was 64%. Imidapril treatment improved cardiac performance, attenuated cardiac remodeling, and reduced morphological changes in the heart and lung. The depressed SL Na+/K+ ATPase and increased SL Na+–Ca2+ exchange activities as well as reduced SR Ca2+ pump and SR Ca2+ release activities in the failing hearts were partially prevented by imidapril. Although changes in gene expression for SL Na+/K+ ATPase isoforms as well as Na+–Ca2+ exchanger and SR phospholamban were attenuated by treatments with imidapril, no alterations in mRNA levels for SR Ca2+ pump proteins and Ca2+ release channels were seen in the untreated or treated rats with heart failure. These results suggest that the beneficial effects of imidapril in CHF may be due to improvements in cardiac performance and changes in SL gene expression.Key words: sarcolemmal Na+/K+ ATPase, Na+–Ca2+ exchange, sarcoplasmic reticulum, heart failure, ACE inhibition.

2008 Thomas W. Smith Memorial Lecture—Protein Kinase C α as a Novel Therapeutic Target for Treating Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jeffrey Molkentin
Keyword(s):  
Heart Failure ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Contractility ◽  
Dominant Negative ◽  
Kinase C ◽  
Novel Therapeutic

We have shown that protein kinase C (PKC) α functions as a proximal regulator of Ca 2+ handling in cardiac myocytes (Braz et al, Nat. Med. 10:248, 2004). Deletion of PKC α in the mouse resulted in augmented sarcoplasmic reticulum Ca 2+ loading, enhanced Ca 2+ transients, and augmented contractility, whereas overexpression of PKCα in the heart blunted contractility. Mechanistically, PKCα regulates Ca 2+ handling by altering inhibitor-1 phosphorylation, which suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and sarcoplasmic reticulum Ca 2+ AT-Pase 2 (SERCA2). Acute inhibition of PKCα with the pharmacologic agents Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work performing heart preparation in wild-type mice, but not in PKC α-deficient mice. Ro-32-0432 also acutely increased cardiac contractility in two different models of heart failure in vivo. Moreover, acute or chronic treatment with Ro-32-8220 in a mouse model of heart failure, due to deletion of the muscle lim protein (MLP) gene, significantly augmented cardiac contractility and restored normal pump function. Adenoviral-mediated gene therapy with a dominant negative PKCα cDNA rescued heart failure in a chronic rat model of postinfarction cardiomyopathy. Moreover, expression of dominant-negative PKCα in cardiac myocytes using a cardiac-specific transgenic system (tetracycline-regulated) also enhanced cardiac contractility and antagonized heart failure due to myocardial infarction injury. Finally, another PKCα/β inhibitor, ruboxistaurin (LY333531), antagonized heart failure after long-term pressure overload in mice. PKCα is the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. Indeed, pharmacological inhibition of PKCα may serve as a novel therapeutic strategy for either enhancing cardiac contractility in the setting of severe functional deterioration or as a long-term treatment option to prevent worsening of heart failure in earlier stages.

Potential Mechanisms Underlying Therapeutic Benefits of Stem Cell for Heart Failure

Nano LIFE ◽  
2019 ◽  
Vol 09 (03) ◽  
pp. 1941004
Author(s):  
Xin Xiong ◽  
Feby Savira ◽  
Kevin W Huang ◽  
Zuoren Yu ◽  
Bing Hui Wang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cardiac Disease ◽  
Cardiac Tissue ◽  
Heart Diseases ◽  
Cardiac Cells ◽  
Therapeutic Benefits ◽  
Disease Therapy ◽  
Underlying Mechanisms

Stem cell therapy has been tested for cardiac disease therapy for decades. Initially, researchers only considered stem cells’ differentiative ability to repair damaged cardiac tissue. However, studies have now uncovered novel mechanisms contributing to stem cell healing properties to repair injured cardiac tissue, including via paracrine signaling and exosome secretions, leading to amelioration of cardiac remodeling and enhancement of proliferation, regeneration and survival of stem cell-derived cardiac cells. Understanding these underlying mechanisms could help researchers utilize stem cells as a therapeutic strategy for cardiac disease effectively and address the current limitations, mainly surrounding its survival and differentiative ability in the cardiac milieu. This review will discuss the known potential mechanisms underlying the role of stem cells in contributing to and for the treatment of heart diseases.

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