Identification of RyR2-PBmice and the effects of transposon insertional mutagenesis of the RyR2 gene on cardiac function in mice

Ryanodine receptor 2 (RyR2) plays an important role in maintaining the normal heart function, and mutantions can lead to arrhythmia, heart failure and other heart diseases. In this study, we successfully identified a piggyBac translocated RyR2 gene heterozygous mouse model (RyR2-PBmice) by tracking red fluorescent protein (RFP) and genotyping PCR. Cardiac function tests showed that there was no significant difference between the RyR2-PBmice and corresponding wild-type mice (WTmice), regardless of whether they were in the basal state or injected with epinephrine and caffeine. However, the sarcoplasmic reticulum Ca2+ content was significantly reduced in the cardiomyocytes of RyR2-PBmice as assessed by measuring caffeine-induced [Ca2+]i transients; the cardiac muscle tissue of RyR2-PBmice displayed significant mitochondrial swelling and focal dissolution of mitochondrial cristae, and the tissue ATP content in the RyR2-PBmice heart was significantly reduced. To further analyze the molecular mechanism behind these changes, we tested the expression levels of related proteins using RT-PCR and Western blot analyses. The mRNA level of RyR2 in RyR2-PBmice cardiac tissue decreased significantly compared with the WTmice, and the protein expression associated with the respiratory chain was also downregulated. These results suggested that the piggyBac transposon inserted into the RyR2 gene substantively affected the structure and function of mitochondria in the mouse cardiomyocytes, leading to disorders of energy metabolism.

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PO-301 Study on the effects of bone marrow-derived stem cells were used in chronic hyperactivity rats to cardiac injury treatment

Exercise Biochemistry Review ◽

10.14428/ebr.v1i5.13373 ◽

2018 ◽

Vol 1 (5) ◽

Author(s):

Lei Xu ◽

YiBo Niu

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Cardiac Function ◽

Test Data ◽

Cardiac Tissue ◽

Heart Function ◽

Training Group ◽

Significant Difference ◽

General Training

Objective overload and long-term overtraining can cause hypoxic and hypoxic damage to the myocardial structure of the body. In recent years, studies have shown that the stem cells promote angiogenesis in vivo, resistance to apoptosis, myocardial stem cell mobilization, and promote its proliferation in paracrine effect, such as vascular distribution. By animal experiments, this study explore MSCMs role in the improvement of heart function and its molecular mechanism to sports injury prevention and postoperative rehabilitation is of great significance of the heart, heart research provides the basis for the motion at the same time support. Methods Wistar rat model of excessive swimming training. Grouping: rats were randomly divided into 4 groups (n=10), quiet feeding group (Q), general training group (ET), over-training group (OT), and MSCMs transplant-over-training group (MOT). Source and preparation of stem cells: the rat autologous bone marrow was extracted 1 day before surgery, and the bone marrow mononuclear cells were isolated by Ficoll density gradient centrifugation. Methods of stem cell transplantation: perfusion via coronary artery in MOT group rats; Test indicators and methods: cardiac tissue was taken after the end of 1d training (group Q, ET and OT), MEF2A factor was tested by rcal-time, gata-4 expression was tested by Western blot, and LVEF value was observed by cardiac color doppler ultrasound (before, after 1w, after 2w and after 3w, respectively). Results MEF2A factor, gata-4 expression and LVEF value of the three groups of samples were detected: (1) compared with MEF2A factor in general training group (ET) and quiet group (Q), gata-4 expression was slightly improved, but there was no significant difference (P>0.05). After 3w, the increase of LVEF value presented significant differences (Pwhile 1w and 2w showed no significant differences compared with the quiet group. (2) comparison between the over-training group (OT) and the quiet group (Q) showed significant differences in MEF2A factor, gata-4 expression, and LVEF decreased value (P0.05) between the two groups after 2w and the quiet group (Q). Cardiac tissue was taken after 2w to observe the expression of MEF2A, and gata-4 was compared with the silent group (Q) without significant difference (P>0.05). Conclusions (1) based on the test data of general training group (ET), reasonable and scientific aerobic exercise can effectively enhance the cardiac function and improve the cardiac activity ability. (2) according to the test data of over-training group (OT), overloading and long-term over-training can lead to hypoxia of heart function and decrease of vitality, resulting in hypoxia and ischemia of the motor heart and damage of cardiac function. (3) according to the observation and test data of the MSCMs transplant-over-training group (MOT), MSCMs transplantation can effectively improve the cardiac function of sports injuries, enhance the cardiac vitality, and repair damaged cells and tissues to a certain extent. It can effectively prevent and treat heart injury caused by overtraining. At the same time, it provides animal experimental research support for the research of sports heart in sports medicine.

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Abstract 126: Peroxisomal Proliferator Activated Receptor Alpha Overexpression in Hypertrophied Cardiomyocytes Restores Mitochondrial Integrity and Function

Circulation Research ◽

10.1161/res.121.suppl_1.126 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Sagartirtha Sarkar ◽

Santanu Rana

Keyword(s):

Energy Demand ◽

Cardiac Tissue ◽

Structural Integrity ◽

Heart Function ◽

Ros Generation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Atp Production ◽

Receptor Alpha ◽

And Function

Cardiac tissue engineering is an interdisciplinary field that engineers modulation of viable molecular milieu to restore, maintain or improve heart function. Myocardial workload (energy demand) and energy substrate availability (supply) are in continual flux to maintain specialized cellular processes, yet the heart has a limited capacity for substrate storage and utilization during pathophysiological conditions. Damage to heart muscle, acute or chronic, leads to dysregulation of cardiac metabolic processes associated with gradual but progressive decline in mitochondrial respiratory pathways resulting in diminished ATP production. The Peroxisome Proliferator Activated Receptor Alpha ( PPARα ) is known to regulate fatty acid to glucose metabolic balance as well as mitochondrial structural integrity. In this study, a non-canonical pathway of PPARα was analyzed by cardiomyocyte targeted PPARα overexpression during cardiac hypertrophy that showed significant downregulation in p53 acetylation as well as GSK3β activation levels. Targeted PPARα overexpression during hypertrophy resulted in restoration of mitochondrial structure and function along with significantly improved mitochondrial ROS generation and membrane potential. This is the first report of myocyte targeted PPARα overexpression in hypertrophied myocardium that results in an engineered heart with significantly improved function with increased muscle mitochondrial endurance and reduced mitochondrial apoptotic load, thus conferring a greater resistance to pathological stimuli within cardiac microenvironment.

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Abstract 339: Long-term AAV6-βARKct Myocardial Gene Therapy Improves Cardiac Function Via Restoration Of β-Adrenergic Receptor Signaling And Neurohormonal Status Of The Failing Heart

Circulation ◽

10.1161/circ.118.suppl_18.s_287-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Giuseppe Rengo ◽

Anastasios Lymperopoulos ◽

Carmela Zincarelli ◽

Maria Donniacuo ◽

Stephen Soltys ◽

...

Keyword(s):

Gene Therapy ◽

Gene Delivery ◽

Cardiac Function ◽

Adrenergic Receptor ◽

Fluorescent Protein ◽

Heart Function ◽

Weight Ratio ◽

Intramyocardial Injection ◽

Molecular Abnormalities ◽

Virus Serotype

BACKGROUND: The up-regulation of G protein-coupled receptor kinase-2 (GRK2) that is present in compromised myocardium contributes to dysfunctional β-adrenergic receptor (βAR) signaling and cardiac function in heart failure (HF). The peptide βARKct, which inhibits the activation of GRK2, has been shown in acute gene transfer experiments to rescue HF. This study was designed to evaluate chronic βARKct expression in post-myocardial infarction (MI) induced HF using stable myocardial gene delivery with adeno-associated virus serotype-6 (AAV6). METHODS AND RESULTS: In 12 week post-MI HF rats, we delivered βARKct or as a control, Green Fluorescent Protein, via direct intramyocardial injection. We also treated groups with concurrent administration of metoprolol. We found robust and long-lasting (up to 12 weeks post-delivery) transgene expression in the left ventricle (LV) and βARKct expression resulted in significantly improved global heart function as LV ejection fraction and ±dP/dt were increased, whereas LV end diastolic diameter and pressure were decreased. At the molecular level, cardiac βAR density and cAMP accumulation significantly improved over control groups. Fibrotic and hypertrophy markers, as well as heart-to-body weight ratio were markedly decreased by βARKct gene therapy indicating active reversal of adverse LV remodeling. For the first time, we found that chronic βARKct expression and normalization of cardiac βAR signaling led to a reduction of circulating levels of cardiotoxic neurohormones (catecholamines and aldosterone) demonstrating a potential additive mechanism of GRK2 inhibition. Concomitant metoprolol administration preserved the gain in inotropy achieved by βARKct, suggesting compatibility of these two therapeutic modalities, however, metoprolol alone only prevented the deterioration of cardiac function in HF. CONCLUSIONS : Chronic cardiac βARKct gene therapy for HF treatment via AAV6-mediated intracardiac gene delivery is feasible and results in improved cardiac function accompanied by restoration of βAR molecular abnormalities and amelioration of neurohormonal status of HF. These findings suggest βARKct gene therapy might be clinically applicable and of significant value for human HF treatment. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

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Abstract 556: Deficiency of Probhitin-1 in Hepatocytes Alters Systemic Glucose Regulation

Circulation Research ◽

10.1161/res.127.suppl_1.556 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Katie Weihbrecht ◽

Jo Mahoney ◽

Ethan J Anderson

Keyword(s):

Insulin Sensitivity ◽

Cardiac Function ◽

Serum Levels ◽

Tolerance Test ◽

Human Thyroid ◽

Specific Loss ◽

Insulin Tolerance ◽

Significant Difference ◽

Glucose Challenge ◽

And Function

Prohibitins 1 and 2 (PHB1 and PHB2) are lipid raft proteins that form a hetero-oligomeric complex known to localize to the cytoplasmic, nuclear, and mitochondrial membranes. These complexes play important roles in pro-survival and metabolic decisions including inflammation. PHB1 is important for mitochondria biogenesis and function and is excreted into the serum. Mice challenged with an intraperitoneal injection of lipopolysaccharide (LPS), a treatment that normally results in decreased cardiac function, show increased serum PHB. Injection of recombinant PHB1 (rPHB1) following LPS injection can rescue cardiac function. Work in our lab with cultured cardiomyocytes and multiple rodent models of severe sepsis supports the hypothesis that PHB1 is a liver-derived acute phase protein. To test this hypothesis, we utilized AAV- Cre recombinase infection driven by human thyroid hormone-binding globulin (TBG), a liver specific promotor (AAV8-TBG-iCre), on our PHB1 floxed mice (PHB1 fl/fl ). This liver specific knockdown of PHB1 allowed us to look at PHB1 levels in the serum of unstressed PHB1 fl/fl mice. We discovered a loss of PHB1 in the liver tissue of floxed mice and significantly lower serum levels of PHB was found in homozygotes compared to wild types. Additionally, mice with liver specific loss of PHB1 show metabolic changes including significant weight loss three weeks following injection and changes to body composition and a trend of decreases in brown fat and inguinal fat mass. In addition to these body changes, we found that liver specific loss resulted in sexual dimorphism in insulin sensitivity. Homozygous males showed a significant difference in their ability to clear glucose following a glucose challenge in a glucose tolerance test. However, following an insulin tolerance test, female homozygotes showed increased insulin sensitivity where males did not. Both males and females show a trend towards attenuated gluconeogenesis following a pyruvate tolerance test. Overall, we have begun to characterize novel findings to the metabolic state of mice lacking PHB1 only in the liver. Our aim is to further explore if these differences are due to the changes in liver PHB1 or due to changes in circulating serum PHB1.

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Cardiac peptide stability, aprotinin and room temperature: importance for assessing cardiac function in clinical practice

Clinical Science ◽

10.1042/cs0970689 ◽

1999 ◽

Vol 97 (6) ◽

pp. 689-695 ◽

Cited By ~ 29

Author(s):

Martin G. BUCKLEY ◽

Neil J. MARCUS ◽

Magdi H. YACOUB

Keyword(s):

Clinical Practice ◽

Cardiac Function ◽

Natriuretic Peptide ◽

Room Temperature ◽

Heart Function ◽

Routine Clinical Practice ◽

Blood Samples ◽

Initial Values ◽

Significant Difference ◽

The Stability

Brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and N-terminal ANP are good research indices of the severity of heart failure. The stability of these peptides at room temperature has become an important factor in assessing their use as indicators of cardiac function in routine clinical practice. Inhibitors such as aprotinin are routinely added in the blood collection process, but may provide no benefit in sample collection and routine clinical practice. We assessed the stability of BNP, ANP and N-terminal ANP in blood samples collected in either the presence or the absence of the protease inhibitor aprotinin. Blood, either with or without aprotinin, was processed immediately (initial; 0 h) and after blood samples had been left for 3 h, 2 days or 3 days at room temperature. These times were chosen to reflect processing in a hospital outpatient clinic (2–3 h), or when posted from general practice (2–3 days). Initial plasma BNP, ANP and N-terminal ANP levels in the absence of aprotinin were 28.2±5.4, 44.2±7.9 and 1997±608 pg/ml respectively, and were not significantly different from initial values in the presence of aprotinin (29.0±5.9, 45.2±8.0 and 2009±579 pg/ml respectively). After 3 h at room temperature, there was a significant fall in ANP in the absence of aprotinin (36.7±7.9 pg/ml; P< 0.005), but not in the presence of aprotinin (41.2±7.6 pg/ml). Both BNP and N-terminal ANP were unchanged in either the absence (BNP, 27.6±5.5 pg/ml; N-terminal ANP, 2099±613 pg/ml) or the presence (BNP, 29.4±5.6 pg/ml; N-terminal ANP, 1988±600 pg/ml) of aprotinin. After 2 days at room temperature, ANP had fallen significantly in both the absence (16.9±3.4 pg/ml) and the presence (24.0±5.0 pg/ml) of aprotinin compared with initial values, and there was a significant difference in ANP levels in the absence and presence of aprotinin (P< 0.001). ANP levels had decreased further after 3 days at room temperature, to 11.9±3.4 pg/ml (no aprotinin) and 20.3±5.0 pg/ml (aprotinin added); these values were significantly different (P = 0.002). In contrast, there was no change in the levels of BNP or N-terminal ANP after 2 or 3 days at room temperature, in either the absence or the presence of aprotinin. These studies indicate that aprotinin adds little benefit to the stability of cardiac peptides at room temperature. Blood samples for BNP and N-terminal ANP measurement used as a test of heart function in hospital clinics and by general practitioners in the community could be taken into blood tubes containing only EDTA as anticoagulant and without the additional step of adding the routinely used inhibitor aprotinin.

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Dynamic changes in G alpha i-2 levels in rat hearts associated with impaired heart function after myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.3.h1073 ◽

1995 ◽

Vol 269 (3) ◽

pp. H1073-H1079 ◽

Cited By ~ 2

Author(s):

B. Shi ◽

J. E. Heavner ◽

K. K. McMahon ◽

J. E. Spallholz

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Heart Function ◽

Late Phase ◽

Control Level ◽

Lag Phase ◽

Rat Hearts ◽

Pressure Development ◽

And Function ◽

Gs Alpha

The objective of this study was to determine if levels and function of Gs alpha and G alpha i-2 in rat hearts change over time following acute myocardial infarction (MI), and if so, whether the changes in G proteins are associated with changes in heart function. As compared with sham-operated controls, the G alpha i-2 level of MI rats did not change at day 1, increased by 64% at day 3 (P < 0.01) and by 55% at day 9 (P < 0.05) accompanied by reduced adenylyl cyclase activity, and returned to control by day 21. By contrast, the Gs alpha level did not change at any time. Cardiac function in MI animals was markedly impaired at days 1, 3, and 9 as evidenced by substantial elevation in LVEDP and reduction in maximum rates of pressure development and relaxation, and was partially restored at day 21. Increased G alpha i-2 level in MI rats correlated significantly to severity of impaired cardiac function. The results show a three-phase dynamic pattern in G alpha i-2 level following acute MI: a lag phase, an increased expression phase associated with marked impairment of heart function, and a late phase in which the expression returns to control level accompanied by partially restored cardiac function.

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Effects of nifedipine on fetal cardiac function in preterm labor

Journal of Perinatal Medicine ◽

10.1515/jpm-2020-0160 ◽

2020 ◽

Vol 48 (7) ◽

pp. 723-727

Author(s):

Osman Yilmaz ◽

Ayhan Şule Göncü

Keyword(s):

Cardiac Function ◽

Preterm Labor ◽

Heart Function ◽

Tertiary Hospital ◽

Cardiac Effect ◽

Fetal Doppler ◽

Fetal Cardiac Function ◽

Sphericity Index ◽

Significant Difference ◽

Doppler Indices

AbstractObjectivesTo evaluate the effects of nifedipine treatment on fetal hemodynamics and cardiac function during preterm labor. This prospective study assessed several quantitative parameters of fetal cardiac circulation and function, and found no significant changes at 48 h after nifedipine treatment. These findings suggest that tocolytic nifedipine may be safe for fetuses. It supports clinicians to use nifedipine treatment for tocolysis without any cardiac effect on the fetus.MethodsA prospective cohort study was conducted at a tertiary hospital between January 2016 and October 2017. A total of 45 pregnant women who required nifedipine for preterm labor were included in this study. Fetal Doppler ultrasound was performed and fetal systolic and diastolic function was measured prior to, and 48 h after, the first nifedipine treatment. Conventional Doppler parameters were used to evaluate fetal heart function and hemodynamic changes. Tricuspid annular plane systolic excursion, mitral annular plane systolic excursion and the sphericity index were also evaluated to assess changes in fetal cardiac morphology.ResultsNo significant changes in fetal Doppler parameters were observed following nifedipine tocolysis. There was no significant difference in the fetal cardiac function parameters of both ventricles before vs. after nifedipine treatment. Tricuspid annular plane systolic excursion, mitral annular plane systolic excursion, and sphericity index values were unchanged following nifedipine treatment.ConclusionsOral administration of nifedipine did not to alter fetal cardiac function or morphology. Fetal cardiac parameters and various Doppler indices were unchanged following nifedipine treatment. Maternal nifedipine treatment does not appear to have any significant effect on fetal cardiac function.

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Abstract 13427: Extracellular Vesicles Improve Heart Function Without Inducing the Generation of New Cardiomyocytes

Circulation ◽

10.1161/circ.142.suppl_3.13427 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Bruna Lima Correa ◽

Nadia El harane ◽

Maria Perotto ◽

Manon Desgres ◽

Chloe Guillas ◽

...

Keyword(s):

Cardiac Function ◽

Extracellular Vesicles ◽

De Novo ◽

Heart Function ◽

Heart Tissue ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Heart Repair ◽

Significant Difference ◽

Improve Heart Function

Introduction: Extracellular Vesicles (EV) recapitulate the benefits of cell therapy for heart repair. Their mechanism of action remains unsettled. Hypothesis: EV may contribute to heart repair by de novo cardiogenesis. Methods: To answer this question, we used 2 bi-transgenic mouse models: the fate-mapping MerCreMer/ZEG and the Mosaic Analysis With Double Markers (MADM). Myocardial infarction was induced by permanent coronary artery ligation. Those with a LVEF ≤ 45% were treated 3 weeks later with EV (from human iPS-derived cardiovascular progenitor cells; 10x10 9 particles) or PBS, injected under echo guidance in the peri-infarcted area (MerCreMer/ZEG: n=15/group and MADM: n=6/group). To track endogenous cardiomyocyte (CM) proliferation, we used EdU labeling in MerCreMer/ZEG delivered by osmotic pumps implanted for 7-10 days post-injection and biphoton microscopy in MADM models. Cardiac function was assessed 4-6 weeks after injection by echocardiography and MRI, blinded to treatment group. Hearts were then subjected to histological and transcriptomic analyses (qPCR and genome-wide microarray). Results: In PBS controls, EF remained stable over time in MerCreMer/ZEG mice and decreased from 34.5% ± 6.0% to 30.7% ± 7.5% in MADM mice by the end of the study. Conversely, EV injections increased EF from 32.1% ± 9.5% to 36.1% ± 7.45 % in MerCreMer/ZEG and from 36.2 %± 8.7% to 40.5% ± 8.9% in MADM mice. A significant difference in the change from baseline was found between EV and controls: 20.7% ± 10.5 % (p=0.048) and 28.0% ± 11.0 %, (p=0.045) for MerCreMer/ZEG and MADM groups, respectively. This improvement was confirmed by MRI in MerCreMer/ZEG mice (p=0.05). Improvement in EF was unrelated to the appearance of new CM, as shown by the absence of difference in TnT+/EdU+/GFP+ cell numbers and the lack of activation of the YAP/TAZ pathway between control and EV groups. However, EV reduced infarct size by 11.9% ± 5.75% (p=0.04), which was accompanied by decreased expression of 4 pro-fibrotic genes (Col1a2, Col3a1, Lox, Col1a2 by qPCR) in heart tissue and a 2.13X overexpression of the anti-fibrotic miRNA 133a-1 compared to controls (n=3/group; p=0.001). Conclusions: EV likely improve cardiac function by modulation of fibrosis rather than by de novo cardiogenesis.

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Tumor-Induced Cardiac Dysfunction: A Potential Role of ROS

Antioxidants ◽

10.3390/antiox10081299 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1299

Author(s):

Priyanka Karekar ◽

Haley N. Jensen ◽

Kathryn L. G. Russart ◽

Devasena Ponnalagu ◽

Sarah Seeley ◽

...

Keyword(s):

Cell Growth ◽

Cardiac Function ◽

Cancer Patients ◽

Cardiac Dysfunction ◽

Heart Function ◽

Heart Diseases ◽

The Body ◽

Cardiac Defects ◽

Mortality And Morbidity ◽

Irregular Cell

Cancer and heart diseases are the two leading causes of mortality and morbidity worldwide. Many cancer patients undergo heart-related complications resulting in high incidences of mortality. It is generally hypothesized that cardiac dysfunction in cancer patients occurs due to cardiotoxicity induced by therapeutic agents, used to treat cancers and/or cancer-induced cachexia. However, it is not known if localized tumors or unregulated cell growth systemically affect heart function before treatment, and/or prior to the onset of cachexia, hence, making the heart vulnerable to structural or functional abnormalities in later stages of the disease. We incorporated complementary mouse and Drosophila models to establish if tumor induction indeed causes cardiac defects even before intervention with chemotherapy or onset of cachexia. We focused on one of the key pathways involved in irregular cell growth, the Hippo–Yorkie (Yki), pathway. We used overexpression of the transcriptional co-activator of the Yki signaling pathway to induce cellular overgrowth, and show that Yki overexpression in the eye tissue of Drosophila results in compromised cardiac function. We rescue these cardiac phenotypes using antioxidant treatment, with which we conclude that the Yki induced tumorigenesis causes a systemic increase in ROS affecting cardiac function. Our results show that systemic cardiac dysfunction occurs due to abnormal cellular overgrowth or cancer elsewhere in the body; identification of specific cardiac defects associated with oncogenic pathways can facilitate the possible early diagnosis of cardiac dysfunction.

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Endoplasmic reticulum proteins in cardiac development and dysfunction

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y09-032 ◽

2009 ◽

Vol 87 (6) ◽

pp. 419-425 ◽

Cited By ~ 17

Author(s):

Daniel Prins ◽

Marek Michalak

Keyword(s):

Endoplasmic Reticulum ◽

Molecular Mechanisms ◽

Cardiac Development ◽

Heart Function ◽

Heart Diseases ◽

Secretory Proteins ◽

Hypoxic Conditions ◽

Catalytic Role ◽

Membrane Bound ◽

And Function

An understanding of cardiac pathologies and the molecular mechanisms thereof is essential for the development of therapies for cardiovascular disease, a common cause of death in Western societies. Investigations into heart diseases have shown that the endoplasmic reticulum and its diverse functions may lie at the center of many cardiac pathologies. Animal models have demonstrated that in numerous cases, faulty endoplasmic reticulum activity is manifested in defective cardiogenesis or impaired heart function. These findings suggest that the endoplasmic and sarcoplasmic reticulum membranes may represent functionally independent organelles responsible for specialized functions in the heart. This review addresses the molecular pathways linking endoplasmic reticulum function and malfunction with impaired cardiac phenotypes. The endoplasmic reticulum affects cardiac development and function through Ca2+-dependent pathways, its catalytic role in the proper folding and targeting of membrane-bound and secretory proteins, and its response to cellular stress events, particularly hypoxic conditions. These pathways present potential novel targets for treatment of cardiac disease.

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