scholarly journals Pachymic Acid Attenuated Doxorubicin-Induced Heart Failure by Suppressing miR-24 and Preserving Cardiac Junctophilin-2 in Rats

2021 ◽  
Vol 22 (19) ◽  
pp. 10710
Author(s):  
Nahla N. Younis ◽  
Alaa Salama ◽  
Mohamed A. Shaheen ◽  
Rana G. Eissa
Keyword(s):  
Electron Microscopy ◽  
Heart Failure ◽  
Fiber Diameter ◽  
Ryanodine Receptors ◽  
Cardiac Contractility ◽  
Histological Assessment ◽  
Contraction Coupling ◽  
Pachymic Acid ◽  
T Tubules ◽  
Mitochondrial Number

Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca2+ in excitation–contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.

scholarly journals Mitochondrial calcium overload is a key determinant in heart failure

2015 ◽  
Vol 112 (36) ◽  
pp. 11389-11394 ◽  
Author(s):  
Gaetano Santulli ◽  
Wenjun Xie ◽  
Steven R. Reiken ◽  
Andrew R. Marks
Keyword(s):  
Heart Failure ◽  
Mitochondrial Function ◽  
Posttranslational Modifications ◽  
Ryanodine Receptors ◽  
Cardiac Contractility ◽  
Major Effect ◽  
Genetic Enhancement ◽  
Macromolecular Complex ◽  
Atp Production

Calcium (Ca2+) released from the sarcoplasmic reticulum (SR) is crucial for excitation–contraction (E–C) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca2+ is essential for optimal function of these organelles. However, Ca2+ accumulation can impair mitochondrial function, leading to reduced ATP production and increased release of reactive oxygen species (ROS). Oxidative stress contributes to heart failure (HF), but whether mitochondrial Ca2+ plays a mechanistic role in HF remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR Ca2+ leak causes mitochondrial Ca2+ overload and dysfunction in a murine model of postmyocardial infarction HF. There are two forms of Ca2+ release channels on cardiac SR: type 2 ryanodine receptors (RyR2s) and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine models harboring RyR2 mutations that either cause or inhibit SR Ca2+ leak, we found that leaky RyR2 channels result in mitochondrial Ca2+ overload, dysmorphology, and malfunction. In contrast, cardiac-specific deletion of IP3R2 had no major effect on mitochondrial fitness in HF. Moreover, genetic enhancement of mitochondrial antioxidant activity improved mitochondrial function and reduced posttranslational modifications of RyR2 macromolecular complex. Our data demonstrate that leaky RyR2, but not IP3R2, channels cause mitochondrial Ca2+ overload and dysfunction in HF.

scholarly journals Morphological Alterations of the Sarcotubular System in Permanent Myopathy of Hereditary Hypokalemic Periodic Paralysis with a Mutation in the CACNA1S Gene

2020 ◽  
Vol 79 (12) ◽  
pp. 1276-1292
Author(s):  
Takamura Nagasaka ◽  
Takanori Hata ◽  
Kazumasa Shindo ◽  
Yoshiki Adachi ◽  
Megumi Takeuchi ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Repair Process ◽  
Periodic Paralysis ◽  
Immunohistochemical Localization ◽  
Morphological Observation ◽  
Hypokalemic Periodic Paralysis ◽  
Morphological Alterations ◽  
Contraction Coupling ◽  
Sarcotubular System ◽  
T Tubules

Abstract We investigated the immunohistochemical localization of several proteins related to excitation-contraction coupling and ultrastructural alterations of the sarcotubular system in biopsied muscles from a father and a daughter in a family with permanent myopathy with hypokalemic periodic paralysis (PMPP) due to a mutation in calcium channel CACNA1S; p. R1239H hetero. Immunostaining for L-type calcium channels (LCaC) showed linear hyper-stained regions indicating proliferation of longitudinal t-tubules. The margin of vacuoles was positive for ryanodine receptor, LCaC, calsequestrin (CASQ) 1, CASQ 2, SR/ER Ca2+-ATPase (SERCA) 1, SERCA2, dysferlin, dystrophin, α-actinin, LC3, and LAMP 1. Electron microscopy indicated that the vacuoles mainly originated from the sarcoplasmic reticulum (SR). These findings indicate impairment of the muscle contraction system related to Ca2+ dynamics, remodeling of t-tubules and muscle fiber repair. We speculate that PMPP in patients with a CACNA1S mutation might start with abnormal SR function due to impaired LCaC. Subsequent induction of muscular contractile abnormalities and the vacuoles formed by fused SR in the repair process including autophagy might result in permanent myopathy. Our findings may facilitate prediction of the pathomechanisms of PMPP seen on morphological observation.

scholarly journals Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Terje R Kolstad ◽  
Jonas van den Brink ◽  
Niall MacQuaide ◽  
Per Kristian Lunde ◽  
Michael Frisk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Ryanodine Receptor ◽  
Release Kinetics ◽  
Ryanodine Receptors ◽  
Cardiac Contractility ◽  
Super Resolution ◽  
Slow Kinetics ◽  
Spark Generation ◽  
Resolution Imaging

Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca2+ sparks (Ca2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca2+ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca2+ leak and slows Ca2+ release kinetics, leading to weakened contraction in this disease.

1178Unsuspected role of the cardiac PKA type I in excitation-contraction coupling and in heart failure development

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Gandon-Renard ◽  
I Bedioune ◽  
S Karam ◽  
A Varin ◽  
P Lechene ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ex Vivo ◽  
Cardiac Contractility ◽  
Cardiac Contraction ◽  
Type I ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Contraction And Relaxation

Abstract The cAMP-dependent protein kinase (PKA) consists of two regulatory (R) and two catalytic (C) subunits and comprises two subtypes, PKAI and PKAII, defined by the nature of their regulatory subunits, RIα and RIIα respectively. Whereas PKAII is thought to play a key role in β-adrenergic (β-AR) regulation of cardiac contractility, the function of PKAI is unclear. To address this question, we generated mice with cardiomyocyte-specific and conditional invalidation of the RIα subunit of PKA. Tamoxifen injection in 8 weeks-old mice resulted in a >70% decrease in RIα protein without modification of other PKA subunits, which was associated with ∼2-fold increased basal PKA activity in RIα-KO mice (p<0.05, N=6/group). This translated into enhanced cardiac contraction and relaxation, as observed in vivo by increased fractional shortening and E-wave velocity (p<0.05, N=10/group) and ex vivo by increased LV pressure and maximal rate of contraction and relaxation (p<0.05, N=9/group). L-type Ca2+ current density was increased in ventricular myocytes from RIα-KO, and β-AR stimulation was decreased by ∼50% (p<0.05, n=38 cells for WT, and, n=40 for RIα-KO). Consistently, Ca2+ transients amplitude and relaxation kinetics were increased, along with increased occurrence of Ca2+ sparks and waves (p<0.05, n=44 cells for WT, and, n=50 for RIα KO). Phosphorylation of Ca2+ channels (CaV1.2), PLB, RyR2 and cMyBP-C at PKA sites was increased >2-fold (p<0.05, N=6/group) in RIα KO without modification of total protein expression. With age, these mice developed a congestive heart failure (HF) phenotype with massive hypertrophy and fibrosis which eventually led to death in 50% of RIα-KO mice at 50 weeks (versus 0% in WT, p<0.01). These results reveal a previously unsuspected role of PKA type I in cardiac excitation-contraction coupling and HF.

scholarly journals The Physiology and Pathophysiology of T-Tubules in the Heart

2021 ◽  
Vol 12 ◽  
Author(s):  
Ingunn E. Setterberg ◽  
Christopher Le ◽  
Michael Frisk ◽  
Jia Li ◽  
William E. Louch
Keyword(s):  
Heart Failure ◽  
Close Contact ◽  
Ryanodine Receptors ◽  
Wall Stress ◽  
Regulatory Proteins ◽  
Ventricular Wall ◽  
Preserved Ejection Fraction ◽  
Ec Coupling ◽  
T Tubules ◽  
Review Current

In cardiomyocytes, invaginations of the sarcolemmal membrane called t-tubules are critically important for triggering contraction by excitation-contraction (EC) coupling. These structures form functional junctions with the sarcoplasmic reticulum (SR), and thereby enable close contact between L-type Ca2+ channels (LTCCs) and Ryanodine Receptors (RyRs). This arrangement in turn ensures efficient triggering of Ca2+ release, and contraction. While new data indicate that t-tubules are capable of exhibiting compensatory remodeling, they are also widely reported to be structurally and functionally compromised during disease, resulting in disrupted Ca2+ homeostasis, impaired systolic and/or diastolic function, and arrhythmogenesis. This review summarizes these findings, while highlighting an emerging appreciation of the distinct roles of t-tubules in the pathophysiology of heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF). In this context, we review current understanding of the processes underlying t-tubule growth, maintenance, and degradation, underscoring the involvement of a variety of regulatory proteins, including junctophilin-2 (JPH2), amphiphysin-2 (BIN1), caveolin-3 (Cav3), and newer candidate proteins. Upstream regulation of t-tubule structure/function by cardiac workload and specifically ventricular wall stress is also discussed, alongside perspectives for novel strategies which may therapeutically target these mechanisms.

scholarly journals T-tubule remodeling in human hypertrophic cardiomyopathy

2020 ◽  
Author(s):  
Giulia Vitale ◽  
Raffaele Coppini ◽  
Chiara Tesi ◽  
Corrado Poggesi ◽  
Leonardo Sacconi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Structural Integrity ◽  
Left Ventricular ◽  
Small Subset ◽  
Excitation Contraction Coupling ◽  
Functional Changes ◽  
Contraction Coupling ◽  
T Tubules ◽  
End Stage

AbstractThe highly organized transverse T-tubule membrane system represents the ultrastructural substrate for excitation–contraction coupling in ventricular myocytes. While the architecture and function of T-tubules have been well described in animal models, there is limited morpho-functional data on T-tubules in human myocardium. Hypertrophic cardiomyopathy (HCM) is a primary disease of the heart muscle, characterized by different clinical presentations at the various stages of its progression. Most HCM patients, indeed, show a compensated hypertrophic disease (“non-failing hypertrophic phase”), with preserved left ventricular function, and only a small subset of individuals evolves into heart failure (“end stage HCM”). In terms of T-tubule remodeling, the “end-stage” disease does not differ from other forms of heart failure. In this review we aim to recapitulate the main structural features of T-tubules during the “non-failing hypertrophic stage” of human HCM by revisiting data obtained from human myectomy samples. Moreover, by comparing pathological changes observed in myectomy samples with those introduced by acute (experimentally induced) detubulation, we discuss the role of T-tubular disruption as a part of the complex excitation–contraction coupling remodeling process that occurs during disease progression. Lastly, we highlight how T-tubule morpho-functional changes may be related to patient genotype and we discuss the possibility of a primitive remodeling of the T-tubule system in rare HCM forms associated with genes coding for proteins implicated in T-tubule structural integrity, formation and maintenance.

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