Abstract 181: Cardiac Hypertrophy And Heart Failure In K-channel Ancillary Subunit Depleted Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Torsten K Roepke ◽  
Ulrike Lisewski ◽  
Leonhard Schleussner ◽  
Carolin Gaertner ◽  
Clemens Koehncke
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Potassium Channel ◽  
Isolated Heart ◽  
Severe Heart Failure ◽  
Calcium Handling ◽  
K Channel ◽  
Sodium Calcium Exchanger ◽  
Down Regulation ◽  
And Function

Down regulation of cardiac K+ currents has been described in hypertrophic heart disease and heart failure. However, so far no mutations in potassium channel genes have been found in patients with cardiac hypertrophy/heart failure. It therefore remains controversial whether K+ current down regulation represents a primary cause of cardiac hypertrophy/heart failure or epiphenomena. KCNE2 is a voltage gated potassium channel ancillary subunit that is associated with inherited and acquired long QT syndrome. We recently developed KCNE2-/- mice. KCNE2-/- mice have normal cardiac morphology and function at 3-6 months of age despite a repolarization defect caused by disruption of IKslow, 1 and Ito, f. However, aged KCNE2-/- mice (12 months and older) develop significant cardiac hypertrophy and severe heart failure assessed by echocardiography, isolated heart (Langendorff) and reduced cellular shortening (IonOptix). Furthermore, after Angiotensin II stimulation 3-6 months old KCNE2-/- mice also develop significant cardiac hypertrophy and fibrosis compared to age-matched KCNE2+/+ siblings. Taqman PCR revealed molecular remodelling in hypertrophied failing KCNE2-/- hearts with induction of the fetal gene program (ANF re-expression), significant up regulation of Sodium-Calcium Exchanger (NCX) and significant down regulation of phospholamban. Alterations in Calcium handling proteins were also recapitulated on protein level by Western Blotting. Furthermore, electrophysiological studies by patch clamp analysis of isolated cardiomyocytes revealed a decrease in current densities of the L-type Ca2+-current and a strongly diminished response to isoprenaline stimulation in hypertrophied failing KCNE2-/- cardiomyocytes. We therefore conclude that primary disruption of repolarizing Kv currents by KCNE2 deletion leads to altered Calcium handling and consecutive induction of cardiac hypertrophy/heart failure.

Abstract 1102: Cardiac-Specific Myosin Light Chain Kinase (MLCK), a Third Member of MLCK Family, Potentiates Sarcomere Formation and Cardiac Contraction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jason Y Chan ◽  
Morihiko Takeda ◽  
Laura E Briggs ◽  
Jonathan T Lu ◽  
Nobuo Horikoshi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Cardiac Hypertrophy ◽  
Light Chain ◽  
Myosin Light Chain Kinase ◽  
Myosin Light Chain ◽  
Contractile Function ◽  
Severe Heart Failure ◽  
Cardiac Contraction

Background: Two myosin light chain kinase (MLCK) proteins, skeletal (encoded by mylk2 gene) and smooth muscle MLCK (encoded by mylk1 gene) have been shown to be expressed in mammals. Human mylk2 has been mapped as a disease locus for familial cardiac hypertrophy (OMIM 606566 ), suggesting that abnormal function of skeletal MLCK stimulates cardiac hypertrophy. While phosphorylation of the putative substrate of skeletal MLCK, myosin light chain 2 (MLC2), is recognized as a key regulator of cardiac contraction, the abundance of skeletal MLCK in the heart is controversial, suggesting the existence of an additional MLCK that is preferentially expressed in cardiac muscle. Methods and Results: We characterized a new kinase named cardiac MLCK that is encoded by a gene homologous to mylk1 and 2 and is specifically expressed in the heart in both atrium and ventricle. Expression of cardiac MLCK was highly regulated by the cardiac homeobox transcription factor, Nkx2.5, in neonatal cardiomyocytes. The overall structure of cardiac MLCK protein is conserved with skeletal and smooth muscle MLCK including putative catalytic and adjacent Ca2+/calmodulin binding domains at the carboxyl-terminus. The amino-terminus is unique without significant homology to other known proteins. Cardiac MLCK phosphorylated MLC2v with a catalytic value of Km=4.3 micro M (Lineweaver-Burk analysis) indicating high affinity of cardiac MLCK to MLC2v, similar to the affinity of skeletal muscle MLCK to skeletal muscle MLC2 and smooth muscle MLCK to smooth muscle MLC2. Adenoviral-mediated overexpression of cardiac MLCK and knockdown of cardiac MLCK using RNAi in cultured cardiomyocytes revealed that cardiac MLCK regulates MLC2v phosphorylation, sarcomere organization and cardiac myocyte contraction. Expression of cardiac MLCK protein was significantly decreased in severe heart failure in vivo (post-myocardial infarction heart failure mouse model). Conclusion: Cardiac MLCK is a new key regulator of cardiac contraction and sarcomere organization. Reduction of cardiac MLCK function leading to decreased phosphorylation of MLC2v may contribute to compromised contractile function in the failing heart.

scholarly journals Atrial Electrophysiological Remodeling and Fibrillation in Heart Failure

2016 ◽  
Vol 10s1 ◽  
pp. CMC.S39713 ◽  
Author(s):  
Sandeep V. Pandit ◽  
Antony J. Workman
Keyword(s):  
Heart Failure ◽  
Molecular Mechanisms ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Ion Currents ◽  
Multiple Variables ◽  
The Individual ◽  
And Function

Heart failure (HF) causes complex, chronic changes in atrial structure and function, which can cause substantial electrophysiological remodeling and predispose the individual to atrial fibrillation (AF). Pharmacological treatments for preventing AF in patients with HF are limited. Improved understanding of the atrial electrical and ionic/molecular mechanisms that promote AF in these patients could lead to the identification of novel therapeutic targets. Animal models of HF have identified numerous changes in atrial ion currents, intracellular calcium handling, action potential waveform and conduction, as well as expression and signaling of associated proteins. These studies have shown that the pattern of electrophysiological remodeling likely depends on the duration of HF, the underlying cardiac pathology, and the species studied. In atrial myocytes and tissues obtained from patients with HF or left ventricular systolic dysfunction, the data on changes in ion currents and action potentials are largely equivocal, probably owing mainly to difficulties in controlling for the confounding influences of multiple variables, such as patient's age, sex, disease history, and drug treatments, as well as the technical challenges in obtaining such data. In this review, we provide a summary and comparison of the main animal and human electrophysiological studies to date, with the aim of highlighting the consistencies in some of the remodeling patterns, as well as identifying areas of contention and gaps in the knowledge, which warrant further investigation.

scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

scholarly journals Seipin Deficiency Accelerates Heart Failure Due to Calcium Handling Abnormalities and Endoplasmic Reticulum Stress in Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoyue Wu ◽  
Xuejing Liu ◽  
Huan Wang ◽  
Zihao Zhou ◽  
Chengzhi Yang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Diastolic Heart Failure ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Related Factors ◽  
Current Decay ◽  
Protein Levels

Seipin deficiency can induce hypertrophic cardiomyopathy and heart failure, which often leads to death in humans. To explore the effects and the possible mechanisms of Seipin deficiency in myocardial remodeling, Seipin knockout (SKO) mice underwent transverse aortic constriction (TAC) for 12 weeks. We found a more severe left ventricular hypertrophy and diastolic heart failure and increases in inflammatory cell infiltration, collagen deposition, and apoptotic bodies in the SKO group compared to those in the wild type (WT) group after TAC. Electron microscopy also showed a more extensive sarcoplasmic reticulum expansion, deformation of microtubules, and formation of mitochondrial lesions in the cardiomyocytes of SKO mice than in those of WT mice after TAC. Compared with the WT group, the SKO group showed increases in endoplasmic reticulum (ER) stress-, inflammation-, and fibrosis-related gene expression, while calcium ion-related factors, such as Serca2a and Ryr, were decreased in the SKO group after TAC. Increased levels of the ER stress-related protein GRP78 and decreased SERCA2a and P-RYR protein levels were detected in the SKO group compared with the WT group after TAC. Slowing of transient Ca2+ current decay and an increased SR Ca2+ content in myocytes were detected in the cardiomyocytes of SKO mice. Adipose tissue transplantation could not rescue the cardiac hypertrophy after TAC in SKO mice. In conclusion, we found that Seipin deficiency could promote cardiac hypertrophy and diastolic heart failure after TAC in mice. These changes may be related to the impairment of myocardial calcium handling, ER stress, inflammation, and apoptosis.

Abstract 389: Human Cardiac Sympathetic Nerves Switch the Neurotransmitter Property from Catecholaminergic to Cholinergic in Patients with Severe Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hideaki Kanazawa ◽  
Masaki Ieda ◽  
Kensuke Kimura ◽  
Takahide Arai ◽  
Haruko Manabe ◽  
...  
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Severe Heart Failure ◽  
Sympathetic Nerves ◽  
Cholinergic Neuron ◽  
Heart Weight ◽  
Control Group ◽  
Down Regulation ◽  
Stellate Ganglia ◽  
Nerve Bundles

[Background] Congestive heart failure (CHF) is characterized by activation of the sympathetic nervous system (SNS) with depletion of norepinephrine (NE) stores, which was initially considered to be the result of excess NE secretion and the loss of noradrenergic nerve terminals. Recent studies however have revealed that it is caused by down regulation of NE synthesis and re-uptake, although the molecular mechanism of down regulation of the sympathetic neuronal function remains unknown. We recently found in an animal model of CHF that the cardiac SNS switches the neurotransmitter property from catecholaminergic to cholinergic, mediated by cytokines LIF and CT-1 secreted from failing myocardium. This study was designed to investigate whether or not this cholinergic transdifferentiation of cardiac SNS occurs in patients with CHF. [Methods & Results] (1) We analyzed 8 samples from patients who died of non-cardiac causes obtained at autopsy (control group), and 8 samples from patients with CHF (CHF group). Five of them died of CHF, and 3 were obtained from native hearts of transplant recipients. (2) The heart weight was significantly higher in the CHF group. (3) The gross morphology of the cardiac SNS did not differ between the two groups. HE and Masson trichrome staining showed disorganized cardiomyocytes and interstitial fibrosis in CHF. (4) Immunostaining for tyrosine hydroxylase (TH, sympathetic nerve marker) revealed that the epicardial nerve bundles and stellate ganglia of the control group had a predominance of TH + nerves, whereas those of CHF group were significantly decreased. (5) Immunostaining for choline transporter (CHT, cholinergic neuron marker) revealed that CHT + neurons were markedly increased in the epicardial nerve bundles of CHF hearts compared with the control group. Some nerves co-expressed both TH and CHT markers. (6) Immunostaining for choline acetyl transferase (ChAT, a cholinergic neuron marker) revealed that stellate ganglia had a lot of ChAT + neurons compared with the control. (7) Nissl staining showed that there was no difference between the two groups in neuron number in the stellate ganglia. [Conclusions] These results indicated that in patients with CHF the cardiac sympathetic nerves also had cholinergic nerve properties.

scholarly journals Statin Therapy for Cardiac Hypertrophy and Heart Failure

2004 ◽  
Vol 52 (4) ◽  
pp. 248-253 ◽  
Author(s):  
James K. Liao
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reductase Inhibitors ◽  
Therapeutic Benefits ◽  
Cardiovascular Cells ◽  
Guanosine Triphosphatase ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
And Function ◽  
Endothelial Nitric Oxide

Cardiac hypertrophy leading to heart failure is a major cause of morbidity and mortality worldwide. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to inhibit cardiac hypertrophy and improve symptoms of heart failure by cholesterol-independent mechanisms. Statins block the isoprenylation and function of members of the Rho guanosine triphosphatase family, such as Rac1 and RhoA. Because Rac1 is a requisite component of reduced nicotinamide adenine dinucleotide phosphate oxidase, which is a major source of reactive oxygen species in cardiovascular cells, the ability of statins to inhibit Rac1-mediated oxidative stress contributes importantly to their inhibitory effects on cardiac hypertrophy. Furthermore, inhibition of RhoA by statins leads to the activation of protein kinase B/Akt and up-regulation of endothelial nitric oxide synthase in the endothelium and the heart. This results in increased angiogenesis and myocardial perfusion, decreased myocardial apoptosis, and improvement in endothelial and cardiac function. Because these effects of statins occur independently of cholesterol lowering, statins may have therapeutic benefits in nonhyperlipidemic patients with cardiac hypertrophy and heart failure.

scholarly journals Bisoprolol reverses down-regulation of potassium channel proteins in ventricular tissues of rabbits with heart failure

2011 ◽  
Vol 25 (4) ◽  
pp. 274-279 ◽  
Author(s):  
Xi Li ◽  
Tingzhong Wang ◽  
Ke Han ◽  
Xiaozhen Zhuo ◽  
Qun Lu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Potassium Channel ◽  
Down Regulation ◽  
Channel Proteins

scholarly journals Excitation Contraction Coupling in Hypertrophy and Failing Heart Cells

2021 ◽  
Vol 271 ◽  
pp. 03008
Author(s):  
Yiqiu Zhou
Keyword(s):  
Heart Failure ◽  
Calcium Release ◽  
Heart Diseases ◽  
Calcium Handling ◽  
Heart Cells ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Failing Heart ◽  
Failure Models ◽  
And Function

The contraction of the heart is dependent on a process named the excitation-contraction coupling (E-C coupling). In hypertrophy and failing heart models, the expression, phosphorylation and function of key calcium handling proteins involved in E-C coupling are altered. It’s important to figure out the relationship changes between calcium channel activity and calcium release from sarcoplasmic reticulum (SR). This review will therefore focus on novel components of E-C coupling dysfunction in hypertrophy and failing heart, such as L-type Ca2+ channel (LCC), ryanodine receptor type-2 channel (RyR2) and SR Ca ATPase (SERCA), and how these molecular modifications altered excitation-contraction coupling. A lot of literature was well read and sorted. Recent findings in E-C coupling during hypertrophy and heart failure were focused on. Most importantly, the electrophysiological and signal pathway data was carefully analyzed. This review summarizes key principles and highlights novel aspects of E-C coupling changes during hypertrophy and heart failure models. Although LCC activity changed little, the loss of notch in action potential, reduced Ca2+ transient amplitude and desynchronized Ca2+ sparks resulted in a decreased contraction strength in hypertrophy and heart failure models. What’s more, L-type Ca2+ current becomes ineffective in triggering RyR2 Ca2+ release from SR and the SR uptake is reduced in some models. It has great meanings in understanding the E-C coupling changes during different heart diseases. Theses novel changes suggest potential therapeutic approaches for certain types of hypertrophy and heart failure.

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