The role of phospholamban and GSK3 in regulating rodent cardiac SERCA function

2020 ◽  
Vol 319 (4) ◽  
pp. C694-C699
Author(s):  
Sophie I. Hamstra ◽  
Kennedy C. Whitley ◽  
Ryan W. Baranowski ◽  
Nigel Kurgan ◽  
Jessica L. Braun ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glycogen Synthase ◽  
Contractile Function ◽  
Cardiac Contractile Function ◽  
Serine Threonine Kinase ◽  
Treatment And Prevention ◽  
Cardiac Contractile ◽  
Plasmic Reticulum ◽  
Serca Pump ◽  
Underlying Mechanisms

Cardiac contractile function is largely mediated by the regulation of Ca2+ cycling throughout the lifespan. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump is paramount to cardiac Ca2+ regulation, and it is well established that SERCA dysfunction pathologically contributes to cardiomyopathy and heart failure. Phospholamban (PLN) is a well-known inhibitor of the SERCA pump and its regulation of SERCA2a—the predominant cardiac SERCA isoform—contributes significantly to proper cardiac function. Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase involved in several metabolic pathways, and we and others have shown that it regulates SERCA function. In this mini-review, we highlight the underlying mechanisms behind GSK3’s regulation of SERCA function specifically discussing changes in SERCA2a and PLN expression and its potential protection against oxidative stress. Ultimately, these recent findings that we discuss could have clinical implications in the treatment and prevention of cardiomyopathies and heart failure.

Abstract 12606: Autophagy is Required for Mitochondrial Biogenesis in the Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Zhonggang Li ◽  
Quanjiang Zhang ◽  
Karla Pires ◽  
E. Dale Abel
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Contractile Function ◽  
Heart Function ◽  
Early Event ◽  
Acid Oxidation ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Deficient Mice

Autophagy is an essential process that maintains cellular homeostasis via lysosomal degradation pathways. Autophagy has been found to be involved in various pathophysiological conditions in the heart, including myocardial hypertrophy and ischemic heart disease. However, the precise mechanism by which autophagy maintains cardiac function in the non-stressed heart is incompletely understood. We generated cardiac-specific ATG3 deficient mice (cATG3 KO mice) by crossing αMHC-Cre mice with floxed ATG3 mice. Relative to their wild type (WT) littermates, cATG3 KO mice revealed reduced ATG3 expression and inhibited autophagy specifically in the heart. At 4 months of age, cATG3 KO mice showed impaired cardiac contractile function, characterized by a 25% reduction in fractional shortening by echocardiography (p <0.01), Moreover, cATG3 KO mice revealed increased lipid accumulation, reduced fatty acid oxidation and impaired mitochondrial respirations in the heart, without evidence of fibrosis or inflammation. Mitochondrial dysfunction in cATG3 KO mice was accompanied with mitochondrial content loss and reduced expression of mitochondrial biogenesis related genes (PGC1α, NRF1, NRF2 and TFAM). Interestingly, autophagy inhibition, induced mitochondrial biogenesis defects and mitochondrial dysfunction in neonatal cATG3 KO mice (1 week old), prior to the onset of cardiac contractile dysfunction and heart failure, suggesting that cardiac mitochondrial dysfunction may be an early event in the progression of heart failure in the autophagy deficient mice. Finally, in response to exercise training mitochondrial biogenesis (PGC1 alpha induction and increased respiration rates) was completely inhibited in ATG3 deficient mice. In conclusion, autophagy is essential for generating signals that promote mitochondrial biogenesis, and is indispensable for normal heart function under basal conditions.

scholarly journals When one says yes and the other says no: Does calcineurin participate in physiologic cardiac hypertrophy?

2021 ◽  
Author(s):  
Jonathan A. Ritchie ◽  
Jun Quan Ng ◽  
Ole J. Kemi
Keyword(s):  
Exercise Training ◽  
Cognitive Processing ◽  
Myocardial Hypertrophy ◽  
Contractile Function ◽  
Real Life ◽  
Current Evidence ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Underlying Mechanisms ◽  
Response To Exercise

Developing engaging activities that build skills for understanding and appreciating research is important for undergraduate and postgraduate science students. Comparing and contrasting opposing research studies does this, and more: it also appropriately for these cohorts challenges higher-level cognitive processing. Here, we present and discuss one such scenario, that of calcineurin in the heart and its response to exercise training. This scenario is further accentuated by the existence of only 2 studies. The background is that regular aerobic endurance exercise training stimulates the heart to physiologically adapt to chronically increase its ability to produce a greater cardiac output to meet the increased demand for oxygenated blood in working muscles, and this happens by 2 main mechanisms: 1) increased cardiac contractile function and 2) physiologic hypertrophy. The major underlying mechanisms have been delineated over the last decades, but one aspect has not been resolved: the potential role of calcineurin in modulating physiologic hypertrophy. This is partly because the existing research has provided opposing and contrasting findings, one line showing that exercise training does activate cardiac calcineurin in conjunction with myocardial hypertrophy, but another line showing that exercise training does not activate cardiac calcineurin even if myocardial hypertrophy is blatantly occurring. Here, we review and present the current evidence in the field and discuss reasons for this controversy. We present real-life examples from physiology research and discuss how this may enhance student engagement and participation, widen the scope of learning, and thereby also further facilitate higher-level cognitive processing.

Cytokines and Cardiac Contractile Function

Circulation ◽  
1997 ◽  
Vol 95 (4) ◽  
pp. 778-781 ◽  
Author(s):  
Ralph A. Kelly ◽  
Thomas W. Smith
Keyword(s):  
Contractile Function ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile

scholarly journals Regulation of Cardiac PKA Signaling by cAMP and Oxidants

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 663
Author(s):  
Friederike Cuello ◽  
Friedrich W. Herberg ◽  
Konstantina Stathopoulou ◽  
Philipp Henning ◽  
Simon Diering
Keyword(s):  
Contractile Function ◽  
Cardiac Contractility ◽  
Cellular Protein ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Main Driver ◽  
Dependent Protein ◽  
Relevant Regulation ◽  
Protein Dysfunction ◽  
Substrate Proteins

Pathologies, such as cancer, inflammatory and cardiac diseases are commonly associated with long-term increased production and release of reactive oxygen species referred to as oxidative stress. Thereby, protein oxidation conveys protein dysfunction and contributes to disease progression. Importantly, trials to scavenge oxidants by systemic antioxidant therapy failed. This observation supports the notion that oxidants are indispensable physiological signaling molecules that induce oxidative post-translational modifications in target proteins. In cardiac myocytes, the main driver of cardiac contractility is the activation of the β-adrenoceptor-signaling cascade leading to increased cellular cAMP production and activation of its main effector, the cAMP-dependent protein kinase (PKA). PKA-mediated phosphorylation of substrate proteins that are involved in excitation-contraction coupling are responsible for the observed positive inotropic and lusitropic effects. PKA-actions are counteracted by cellular protein phosphatases (PP) that dephosphorylate substrate proteins and thus allow the termination of PKA-signaling. Both, kinase and phosphatase are redox-sensitive and susceptible to oxidation on critical cysteine residues. Thereby, oxidation of the regulatory PKA and PP subunits is considered to regulate subcellular kinase and phosphatase localization, while intradisulfide formation of the catalytic subunits negatively impacts on catalytic activity with direct consequences on substrate (de)phosphorylation and cardiac contractile function. This review article attempts to incorporate the current perception of the functionally relevant regulation of cardiac contractility by classical cAMP-dependent signaling with the contribution of oxidant modification.

scholarly journals Neuronostatin inhibits cardiac contractile function via a protein kinase A- and JNK-dependent mechanism in murine hearts

2009 ◽  
Vol 297 (3) ◽  
pp. R682-R689 ◽  
Author(s):  
Yinan Hua ◽  
Heng Ma ◽  
Willis K. Samson ◽  
Jun Ren
Keyword(s):  
Contractile Function ◽  
Peptide Hormone ◽  
Left Ventricular ◽  
Maximal Velocity ◽  
Cardiac Contractile Function ◽  
Mechanical Responses ◽  
Cardiac Contractile ◽  
Short Term Exposure ◽  
The Impact ◽  
Dependent Mechanism

Neuronostatin, a newly identified peptide hormone sharing the same precursor with somatostatin, exerts multiple pharmacological effects in gastrointestinal tract, hypothalamus, and cerebellum. However, the cardiovascular effect of neuronostatin is unknown. The aim of this study was to elucidate the impact of neuronostatin on cardiac contractile function in murine hearts and isolated cardiomyocytes. Short-term exposure of neuronostatin depressed left ventricular developed pressure (LVDP), maximal velocity of pressure development (±dP/d t), and heart rate in Langendorff heart preparation. Consistently, neuronostatin inhibited peak shortening (PS) and maximal velocity of shortening/relengthening (±dL/d t) without affecting time-to-PS (TPS) and time-to-90% relengthening (TR90) in cardiomyocytes. The neuronostatin-elicited cardiomyocyte mechanical responses were mimicked by somatostatin, the other posttranslational product of preprosomatostatin. Furthermore, the neuronostatin-induced cardiomyocyte mechanical effects were ablated by the PKA inhibitor H89 (1 μM) and the Jun N-terminal kinase (JNK) inhibitor SP600125 (20 μM). The PKC inhibitor chelerythrine (1 μM) failed to alter neuronostatin-induced cardiomyocyte mechanical responses. To the contrary, chelerythrine, but not H89, abrogated somatostatin-induced cardiomyocyte contractile responses. Our results also showed enhanced c-fos and c-jun expression in response to neuronostatin exposure (0.5 to 2 h). Taken together, our data suggest that neuronostatin is a peptide hormone with overt cardiac depressant action. The neuronostatin-elicited cardiac contractile response appears to be mediated, at least in part, through a PKA- and/or JNK-dependent mechanism.

Sign in / Sign up

Export Citation Format

Share Document