The complex network of mTOR signalling in the heart

2021 ◽  
Author(s):  
Sebastiano Sciarretta ◽  
Maurizio Forte ◽  
Giacomo Frati ◽  
Junichi Sadoshima
Keyword(s):  
Cardiovascular System ◽  
Cardiac Development ◽  
Metabolic Stress ◽  
Pressure Overload ◽  
Current Data ◽  
Loss Of Function ◽  
Extracellular Signals ◽  
Mtorc1 Activation ◽  
Mtor Modulation ◽  
Mtor Signalling

Abstract The mechanistic target of rapamycin (mTOR) integrates several intracellular and extracellular signals involved in the regulation of anabolic and catabolic processes. mTOR assembles into two macromolecular complexes, named mTORC1 and mTORC2, which have different regulators, substrates and functions. Studies of gain- and loss-of-function animal models of mTOR signalling revealed that mTORC1/2 elicits both adaptive and maladaptive functions in the cardiovascular system. Both mTORC1 and mTORC2 are indispensable for driving cardiac development and cardiac adaption to stress, such as pressure overload. However, persistent and deregulated mTORC1 activation in the heart is detrimental during stress and contributes to the development and progression of cardiac remodelling and genetic and metabolic cardiomyopathies. In this review, we discuss the latest findings regarding the role of mTOR in the cardiovascular system, both under basal conditions and during stress, such as pressure overload, ischemia, and metabolic stress. Current data suggest that mTOR modulation may represent a potential therapeutic strategy for the treatment of cardiac diseases.

scholarly journals MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

Stresses ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 30-47
Author(s):  
Maria Mortoglou ◽  
David Wallace ◽  
Aleksandra Buha Buha Djordjevic ◽  
Vladimir Djordjevic ◽  
E. Damla Arisan ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Metabolic Stress ◽  
Resistance Mechanisms ◽  
Current Data ◽  
Cellular Damage ◽  
Ductal Adenocarcinoma ◽  
Aberrant Expression ◽  
Metabolic Alterations ◽  
Limited Effectiveness ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.

Abstract 791: A Critical Role for Bmper (BMP-binding Endothelial cell precursor-derived Regulator) in Cardiac Muscle Mass Regulation during Development and Pressure Overload Induced Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Monte Willis ◽  
Rongqin Ren ◽  
Cam Patterson
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Muscle Mass ◽  
Cardiac Development ◽  
Critical Role ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Fractional Shortening

Bone morphogenetic proteins (BMPs) of the TGF-beta superfamily, have been implicated in multiple processes during cardiac development. Our laboratory recently described an unprecedented role for Bmper in antagonizing BMP-2, BMP-4, and BMP-6. To determine the role of Bmper on cardiac development in vivo, we created Bmper null (Bmper −/−) mice by replacing exons 1 and 2 with GFP. Since Bmper −/− mice are perinatally lethal, we determined pre-natal cardiac function of Bmper −/− mice in utero just before birth. By echocardiography, E18.5 Bmper −/− embryos had decreased cardiac function (24.2 +/− 8.1% fractional shortening) compared to Bmper +/− and Bmper +/+ siblings (52.2 +/− 1.6% fractional shortening) (N=4/group). To further characterize the role of Bmper on cardiac function in adult mice, we performed echocardiography on 8-week old male and female Bmper +/− and littermate control Bmper +/+. Bmper +/− mice had an approximately 15% decrease in anterior and posterior wall thickness compared to sibling Bmper +/+ mice at baseline (n=10/group). Cross-sectional areas of Bmper +/− cardiomyocytes were approximately 20% less than wild type controls, indicating cardiomyocyte hypoplasia in adult Bmper +/− mice at baseline. Histologically, no significant differences were identified in representative H&E and trichrome stained adult Bmper +/− and Bmper +/+ cardiac sections at baseline. To determine the effects of Bmper expression on the development of cardiac hypertrophy, both Bmper +/− and Bmper +/+ sibling controls underwent transaortic constriction (TAC), followed by weekly echocardiography. While a deficit was identified in Bmper +/− mice at baseline, both anterior and posterior wall thicknesses increased after TAC, such that identical wall thicknesses were identified in Bmper +/− and Bmper +/+ mice 1–4 weeks after TAC. Notably, cardiac function (fractional shortening %) and histological evaluation revealed no differences between Bmper +/− and Bmper +/+ any time after TAC. These studies identify for the first time that Bmper expression plays a critical role in regulating cardiac muscle mass during development, and that Bmper regulates the development of hypertrophy in response to pressure overload in vivo.

The Drosophila dCREB-A gene is required for dorsal/ventral patterning of the larval cuticle

Development ◽  
1997 ◽  
Vol 124 (1) ◽  
pp. 181-193 ◽  
Author(s):  
D.J. Andrew ◽  
A. Baig ◽  
P. Bhanot ◽  
S.M. Smolik ◽  
K.D. Henderson
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Signaling Cascades ◽  
Loss Of Function ◽  
Larval Cuticle ◽  
Extracellular Signals ◽  
Patterning Genes ◽  
Lateral Structures ◽  
Cuticular Structures

We report on the characterization of the first loss-of-function mutation in a Drosophila CREB gene, dCREB-A. In the epidermis, dCREB-A is required for patterning cuticular structures on both dorsal and ventral surfaces since dCREB-A mutant larvae have only lateral structures around the entire circumference of each segment. Based on results from epistasis tests with known dorsal/ventral patterning genes, we propose that dCREB-A encodes a transcription factor that functions near the end of both the DPP- and SPI-signaling cascades to translate the corresponding extracellular signals into changes in gene expression. The lateralizing phenotype of dCREB-A mutants reveals a much broader function for CREB proteins than previously thought.

scholarly journals Adenylyl cyclase type 5 protein expression during cardiac development and stress

2009 ◽  
Vol 297 (5) ◽  
pp. H1776-H1782 ◽  
Author(s):  
Che-Lin Hu ◽  
Rachna Chandra ◽  
Hui Ge ◽  
Jayashree Pain ◽  
Lin Yan ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Ventricular Hypertrophy ◽  
Cardiac Development ◽  
Mammalian Species ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Receptor Stimulation ◽  
Specific Antibodies ◽  
The Brain

Adenylyl cyclase (AC) types 5 and 6 (AC5 and AC6) are the two major AC isoforms expressed in the mammalian heart that mediate signals from β-adrenergic receptor stimulation. Because of the unavailability of isoform-specific antibodies, it is difficult to ascertain the expression levels of AC5 protein in the heart. Here we demonstrated the successful generation of an AC5 isoform-specific mouse monoclonal antibody and studied the expression of AC5 protein during cardiac development in different mammalian species. The specificity of the antibody was confirmed using heart and brain tissues from AC5 knockout mice and from transgenic mice overexpressing AC5. In mice, the AC5 protein was highest in the brain but was also detectable in all organs studied, including the heart, brain, lung, liver, stomach, kidney, skeletal muscle, and vascular tissues. Western blot analysis showed that AC5 was most abundant in the neonatal heart and declined to basal levels in the adult heart. AC5 protein increased in the heart with pressure-overload left ventricular hypertrophy. Thus this new AC5 antibody demonstrated that this AC isoform behaves similarly to fetal type genes, such as atrial natriuretic peptide; i.e., it declines with development and increases with pressure-overload hypertrophy.

The effect of antidiabetic medications on the cardiovascular system: a critical appraisal of current data

HORMONES ◽  
2018 ◽  
Vol 17 (1) ◽  
pp. 83-95 ◽  
Author(s):  
Panagiotis Anagnostis ◽  
Pavlos Siolos ◽  
Konstantinos Christou ◽  
Nifon K. Gkekas ◽  
Nikoletta Kosmidou ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Critical Appraisal ◽  
Current Data ◽  
System A

Abstract 88: A Crucial Role of BAG3 in Preventing Dilated Cardiomyopathy

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Xi Fang ◽  
Julius Bogomolovas ◽  
Wei Zhang ◽  
Tongbin Wu ◽  
Canzhao Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Protein Quality ◽  
Contractile Function ◽  
Metabolic Stress ◽  
Insoluble Fraction ◽  
Therapeutic Benefit ◽  
Loss Of Function ◽  
Specific Subset

Defective protein quality control (PQC) systems are implicated in multiple diseases, with molecular chaperones/co-chaperones being critical to PQC. Cardiomyocytes are constantly challenged by mechanical and metabolic stress, placing great demand on the PQC system. Mutations and downregulation of the co-chaperone protein B cl-2- a ssociated athano g ene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to Dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and mechanisms by which the E455K mutation lead to DCM remained obscure. Here, we found that cardiac-specific BAG3 knockout (CKO) and cardiac-specific E455K BAG3 knockin mice developed DCM. Comparable phenotypes in the two mutants demonstrated that the E455K mutation resulted in loss-of-function, and experiments revealed that the E455K mutation disrupted interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a specific subset of proteins required for metabolic and contractile function of cardiomyocytes was enriched in the insoluble fraction. Together, these observations suggested that interaction between BAG3 and HSP70 was essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide new insight into the pathogenesis of heart failure caused by defects in BAG3 pathways, suggesting that increasing protein levels of BAG3 may be of therapeutic benefit in heart failure.

Abstract P477: A Novel SMYD1 Variant (c.302A>G) Leads To Dilated Cardiomyopathy And Biventricular Heart Failure.

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Marta Szulik ◽  
Miguel Reyes-Mugica ◽  
Daniel F Marker ◽  
Lina Ghaloul-Gonzalez ◽  
Sarah Franklin
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Cardiac Tissue ◽  
De Novo ◽  
Cardiac Development ◽  
Left Ventricular ◽  
Histopathological Analysis ◽  
Loss Of Function ◽  
Adult Mice ◽  
Heterozygous Variant

The lysine methyltransferase SMYD1 was first identified in mice and shown to be important for embryonic cardiac development. Subsequently, we reported the first analysis of SMYD1 in adult myocardium and demonstrated that cardiomyocyte-specific loss of SMYD1 lead to progressive cardiac hypertrophy and heart failure, and showed that this enzyme is necessary to maintain metabolic homeostasis through transcriptional regulation of mitochondrial energetics in adult mice. While SMYD1 has been the subject of several additional studies in zebrafish and mice, since it was first identified, only in the last few years have human patients been identified with variants in the SMYD1 gene thought to be responsible for their cardiomyopathies. Specifically, two patients have been identified to date, the first patient displaying hypertrophic cardiomyopathy had a de novo heterozygous variant (c.814T>C) and the second patient with left ventricular non-compaction cardiomyopathy and arrhythmias had a truncating heterozygous variant (c.675delA). Here we report a third patient with biventricular heart failure containing a homozygous variant (c.302A>G; p.Asn101S) in the SMYD1 gene which was identified by a whole exome sequencing. Our histopathological analysis of cardiac tissue and skeletal muscle from the proband showed abnormalities in myofibrillar organization in both cardiac and skeletal muscle suggesting that SMYD1 is necessary for sarcomere assembly and organization. In addition, we observe markedly abnormal myocardium with extensive fibrosis and multifocal calcification, and our ultrastructural (EM) analysis revealed presence of abnormal mitochondria with reduced and irregular or lost cristae. Lastly, we have performed structural modeling of SMYD1 containing the p.Asn101Ser variant (N101S) and report how this variant may affect the enzymatic activity of SMYD1 due to its proximity to the substrate binding site. The identification of this novel variant constitutes the third patient with a SMYD1 variant displaying cardiomyopathy and provides insights into the molecular functionality of this protein. In addition, this is the first analysis of tissue from a patient expressing a SMYD1 variant which provides critical insights into the role of SMYD1 in the heart and how loss of function mutations can effect cardiac physiology.

scholarly journals Cardiovascular Pleiotropic Effects of Natriuretic Peptides

2019 ◽  
Vol 20 (16) ◽  
pp. 3874 ◽  
Author(s):  
Forte ◽  
Madonna ◽  
Schiavon ◽  
Valenti ◽  
Versaci ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Vascular System ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Pleiotropic Effects ◽  
Current Evidence ◽  
Loss Of Function ◽  
Cardiac Phenotype

Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water–salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.

Expression and cellular distribution of heat-shock and nuclear oncogene proteins in rat hearts

1991 ◽  
Vol 261 (5) ◽  
pp. H1443-H1451 ◽  
Author(s):  
L. H. Snoeckx ◽  
F. Contard ◽  
J. L. Samuel ◽  
F. Marotte ◽  
L. Rappaport
Keyword(s):  
Heat Shock ◽  
Cardiac Development ◽  
Pressure Overload ◽  
Adult Rats ◽  
Coronary Smooth Muscle ◽  
Rat Hearts ◽  
Nonmuscle Cells ◽  
Ontogenic Development ◽  
Coronary Endothelium ◽  
Myocardial Muscle

An early, transient accumulation of mRNAs of the protooncogenes c-fos and c-myc and the heat-shock protein HSP70 has been described in hypertrophying rat hearts. It is unclear 1) in which cardiac cell type-these gene activations occur and 2) whether the corresponding proteins are translated. We studied protein expression in rat hearts during ontogenic development and under stress conditions associated with pressure overload with the use of immunofluorescent techniques. During cardiac development no HSP70 could be detected. c-Fos was expressed consistently after birth but only in coronary smooth muscle cells, and c-Myc was found exclusively in adult coronary endothelium and myocardial nonmuscle cells. In adult rats, HSP70 and, to a lesser extent, c-Fos were induced in myocardial muscle and some nonmuscle cells within 3 h following methohexital sodium anesthesia. A similar, more intense immunolabeling of these peptides was observed after thoracotomy and/or aortic stenosis. The coronary c-Fos and c-Myc labeling remained unchanged in these conditions. Thus the expression in cardiac muscle and nonmuscle cells of the three peptides differs and depends on different triggers.

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