Abstract P056: RalGDS-Dependent Cardiomyocyte Autophagy in Load-Induced Ventricular Hypertrophy

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Oktay F Rifki ◽  
Brian O Bodemann ◽  
Michael A White ◽  
Joseph A Hill
Keyword(s):  
Membrane Trafficking ◽  
Pressure Overload ◽  
Small Gtpases ◽  
Heart Weight ◽  
Critical Feature ◽  
Mtor Inhibition ◽  
Hypertrophic Growth ◽  
Neonatal Cardiomyocytes ◽  
Cardiomyocyte Autophagy ◽  
Contractile Performance

Background: Recent work has demonstrated that autophagy, a phylogenetically conserved, lysosome-mediated pathway of protein degradation, is a key participant in pathological cardiac remodeling. One common feature of cell growth and autophagy is membrane biogenesis and processing. The exocyst, an octomeric protein complex involved in vesicle trafficking, is implicated in numerous cellular processes, yet its role in cardiomyocyte plasticity is unknown. Here, we set out to explore the role of small G protein-dependent membrane trafficking in stress-induced cardiomyocyte remodeling and autophagy. Methods and Results: Hearts from mice lacking RalGDS ( Ralgds -/- ), a guanine exchange factor (GEF) for the Ral family of small GTPases, were similar to wild-type (WT) littermates in terms of ventricular structure, contractile performance, and gene expression. However, Ralgds -/- hearts manifested a blunted growth response (p<0.05) to TAC-mediated pressure-overload stress as determined by heart weight to body weight ratios (HW/BW; WT, sham: 5.00 ± 0.21 mg/g, n=9; TAC: 6.93 ± 0.29, n=13; Ralgds -/- sham: 4.87 ± 0.19, n=6, TAC: 5.86 ± 0.10, n=6). Ventricular chamber size and contractile performance were unchanged in response to TAC in both genotypes. Interestingly, TAC-induced activation of the fetal gene program was similar in both genotypes despite the relative lack of hypertrophic growth in mutant hearts. Ralgds -/- mice also exhibited diminished load-induced cardiomyocyte autophagy. Consistent with the TAC findings, Ralgds -/- mice manifested a blunted autophagic response to 24-hour fasting, suggesting a generalized defect in autophagy. To explore underlying mechanisms, we tested in cultured neonatal cardiomyocytes two isoforms of Ral that are downstream of RalGDS (RalA, RalB) and whose actions are mediated by the exocyst. In these experiments, mTOR inhibition was maintained in response to starvation and rapamycin despite RalA or RalB knockdown; however, autophagy was diminished only in NRCM's with RalB knockdown, implicating RalB as required for cardiomyocyte autophagy. Conclusions: Together, these data implicate RalGDS-mediated induction of autophagy as a critical feature of load-induced cardiac hypertrophy.

Contractile behavior of rat myocardium after reversal of hypertensive hypertrophy

1982 ◽  
Vol 242 (5) ◽  
pp. H882-H889 ◽  
Author(s):  
J. M. Capasso ◽  
J. E. Strobeck ◽  
A. Malhotra ◽  
J. Scheuer ◽  
E. H. Sonnenblick
Keyword(s):  
Myocardial Hypertrophy ◽  
Applied Pressure ◽  
Pressure Overload ◽  
Heart Weight ◽  
Biochemical Alterations ◽  
Time To Peak ◽  
Velocity Of Shortening ◽  
Significant Depression ◽  
Contractile Performance ◽  
Biochemical Abnormalities

The effects of renovascular hypertension and its reversal on the contractile performance of papillary muscles from rats has been examined. Hypertension of 10 wk duration caused a 48% increase in heart weight and significant prolongations of isometric time to peak tension (TPT), time to half relaxation, and time to peak shortening (TPS). A significant depression in the velocity of shortening was observed in the 10-wk group. However, muscles from hypertensive rats were still able to maintain normal levels of peak isometric developed tension and peak shortening; this may be due to the observed prolongation of TPT and TPS, respectively. In addition, calcium-activated actomyosin ATPase activity was depressed in hearts of hypertensive animals. Reversal of hypertension was studied at 20 wk after the onset of hypertension (10 wk of hypertension followed by 10 wk of normotension). Contractile and biochemical alterations observed in hypertensive animals were reversed in rats undergoing this regime. Thus reversal of a gradually applied pressure overload resulted in the regression of mechanical and biochemical abnormalities associated with the pressure overload myocardial hypertrophy.

Abstract 36: Administration of 17β-Estradiol in C57Bl/6N Female Mice Leads to Cardiac Atrophy and Dysfunction via a β-Catenin Mechanism

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Georgios Kararigas ◽  
Laura C Zelarayan ◽  
Karl Toischer ◽  
Gerd Hasenfuss ◽  
Hubertus Jarry ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Structural Changes ◽  
Ring Finger ◽  
Pressure Overload ◽  
Heart Weight ◽  
Independent Manner ◽  
Cross Sectional ◽  
Hypertrophic Growth ◽  
Cardiac Atrophy ◽  
17Β Estradiol

The steroid hormone 17β-estradiol (E2) regulates several biological processes. In contrast to its anti-hypertrophic effects under pressure overload, we recently found that E2 induced physiological hypertrophic growth in healthy C57Bl/6J mice but not C57Bl/6N mice. Here, we aimed at the characterization of the effects of E2 in C57Bl/6N mice and tested the hypothesis that β-catenin mediates these E2 effects. Following ovariectomy, 2-month-old C57Bl/6N wild-type and cardiac-specific β-catenin-deleted (β-cat Δex2-6 ) mice were randomized to an E2-containing or soy-free (control, CON) diet ( n = 7-13/group). Cardiac function was examined by echocardiography following established procedures. The 3-month physiological dose of E2 led to a higher relative uterus weight compared with CON ( P < 0.001) in both WT and β-cat Δex2-6 mice. The relative heart weight was significantly reduced by E2 compared with CON in WT mice ( P < 0.001), while there was no significant effect in β-cat Δex2-6 mice. Cardiomyocyte cross-sectional area was also significantly decreased by E2 ( n = 5-7/group; P < 0.001) compared with CON in WT mice, while there was no significant effect in β-cat Δex2-6 mice. Echocardiography revealed a significant decrease in septum width ( P < 0.001) and posterior wall thickness ( P < 0.01) in E2 treated WT mice compared with CON, while there was no significant effect in β-cat Δex2-6 mice ( n = 8/group). These E2-induced structural changes in WT mice were accompanied by a significant decrease in cardiac function, namely a 23% decrease in fractional shortening compared with CON ( P < 0.05), while there was no significant effect in β-cat Δex2-6 mice. Immunoblotting revealed a significant increase in the levels of the ubiquitin ligase and key regulator of proteasome-dependent protein degradation muscle-specific RING finger protein 1 (MuRF1) by E2 compared with CON in WT mice ( P < 0.05), while there was no significant effect in β-cat Δex2-6 mice. Although we hypothesized increased autophagic activity, we found no effect on the autophagy-related protein LC3 in WT or β-cat Δex2-6 mice. In conclusion, our surprising findings show that E2 leads to cardiac atrophy and dysfunction in C57Bl/6N mice via a β-catenin mechanism seemingly in an autophagy-independent manner.

Abstract 241: Cardiac-Specific Overexpression of Runx2 Mediates Cardiac Hypertrophy and Dysfunction in Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Hiroyuki Nakayama ◽  
Tatsuto Hamatani ◽  
Shohei Kumagai ◽  
Kota Tonegawa ◽  
Tomomi Yamashita ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Premature Death ◽  
Heart Weight ◽  
Pcr Analysis ◽  
Marker Genes ◽  
Hypertrophic Response ◽  
Neonatal Cardiomyocytes

Backgrounds: Recent studies demonstrated that the osteopontin (OPN), an acid phosphoprotein plays pivotal roles in cardiac hypertrophy and failure. An osteogenic transcription factor Runx2 regulates the expression of OPN in osteoblasts. In the present study, we examined the pathological role of Runx2 in cardiac hypertrophy and failure. Methods and Results: Runx2 expression was detected in neonatal cardiomyocytes and upregulated in heart 14 days after myocardial infarction (MI) as well as 7days after transverse aortic constriction (TAC) procedures. To determine the functional role of Runx2 in heart, we generated transgenic mice (TG) with inducible cardiac-specific overexpression of Runx2. Two TG lines (low and high) were obtained and high-expressing TG (HE-TG) showed premature death within 8 weeks of age specifically in male mice. At two months of age, the survived male and female HE-TG displayed significant increases in heart weight/body weight ratio (mg/g) compared to controls (control; 4.95±0.26, n=6 vs HE-TG; 6.63±0.12, n=5, p<.05). Consistent with those results, the expression of hypertrophic marker genes such as atrial natriuretic factor (ANF) and αskeletal actin significantly increased in HE-TG heart assessed by real-time RT-PCR analysis. In addition, HE-TG mice demonstrated decreased fractional shortening assessed by echocardiography (control; 44.1±1.89%, n=9 vs HE-TG; 23.9±3.48%, n=7, p<.05). HE-TG mice demonstrated significantly lower heart rate (control; 630±18 bpm, vs HE-TG; 350±74 bpm, n=3 each, p<.05) and complete atrioventricular block by telemetry analysis. In response to pressure overload, low expressing TG (LE-TG) demonstrated higher mortality and enhanced cardiac hypertrophic response after TAC (control; 6.20±0.23, n=6 vs LE-TG; 6.90±0.26, n=4, p<.05). Conclusions: Targeted expression of Runx2 in heart mediates cardiac dysfunction and hypertrophy in mice. Thus, Runx2 could be a novel therapeutic target for heart failure.

scholarly journals Interactions of Lipid Droplets with the Intracellular Transport Machinery

2021 ◽  
Vol 22 (5) ◽  
pp. 2776
Author(s):  
Selma Yilmaz Dejgaard ◽  
John F. Presley
Keyword(s):  
Membrane Trafficking ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Neutral Lipids ◽  
Small Gtpases ◽  
Lipid Phase ◽  
Intracellular Organelles ◽  
And Function ◽  
Lipid Phase Separation ◽  
Endocytic Pathways

Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.

scholarly journals Small GTPases of the Rab and Arf Families: Key Regulators of Intracellular Trafficking in Neurodegeneration

2021 ◽  
Vol 22 (9) ◽  
pp. 4425
Author(s):  
Alazne Arrazola Arrazola Sastre ◽  
Miriam Luque Luque Montoro ◽  
Hadriano M. Lacerda ◽  
Francisco Llavero ◽  
José L. Zugaza
Keyword(s):  
Membrane Trafficking ◽  
Neurodegenerative Disorders ◽  
Synaptic Vesicles ◽  
Intracellular Trafficking ◽  
Small Gtpases ◽  
Constant Flow ◽  
Parkinson’S Diseases ◽  
The Central Nervous System ◽  
Arf Gtpases

Small guanosine triphosphatases (GTPases) of the Rab and Arf families are key regulators of vesicle formation and membrane trafficking. Membrane transport plays an important role in the central nervous system. In this regard, neurons require a constant flow of membranes for the correct distribution of receptors, for the precise composition of proteins and organelles in dendrites and axons, for the continuous exocytosis/endocytosis of synaptic vesicles and for the elimination of dysfunctional proteins. Thus, it is not surprising that Rab and Arf GTPases have been associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Both pathologies share characteristics such as the presence of protein aggregates and/or the fragmentation of the Golgi apparatus, hallmarks that have been related to both Rab and Arf GTPases functions. Despite their relationship with neurodegenerative disorders, very few studies have focused on the role of these GTPases in the pathogenesis of neurodegeneration. In this review, we summarize their importance in the onset and progression of Alzheimer’s and Parkinson’s diseases, as well as their emergence as potential therapeutical targets for neurodegeneration.

scholarly journals Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 805
Author(s):  
Christiane Ott ◽  
Tobias Jung ◽  
Sarah Brix ◽  
Cathleen John ◽  
Iris R. Betz ◽  
...  
Keyword(s):  
Cardiomyocyte Hypertrophy ◽  
Aortic Constriction ◽  
Cell Contractility ◽  
Neonatal Cardiomyocytes ◽  
Cardiomyocyte Contractility ◽  
Cardioprotective Effects ◽  
Modified Proteins ◽  
Cardiomyocyte Autophagy

Cardiac remodeling and contractile dysfunction are leading causes in hypertrophy-associated heart failure (HF), increasing with a population’s rising age. A hallmark of aged and diseased hearts is the accumulation of modified proteins caused by an impaired autophagy-lysosomal-pathway. Although, autophagy inducer rapamycin has been described to exert cardioprotective effects, it remains to be shown whether these effects can be attributed to improved cardiomyocyte autophagy and contractility. In vivo hypertrophy was induced by transverse aortic constriction (TAC), with mice receiving daily rapamycin injections beginning six weeks after surgery for four weeks. Echocardiographic analysis demonstrated TAC-induced HF and protein analyses showed abundance of modified proteins in TAC-hearts after 10 weeks, both reduced by rapamycin. In vitro, cardiomyocyte hypertrophy was mimicked by endothelin 1 (ET-1) and autophagy manipulated by silencing Atg5 in neonatal cardiomyocytes. ET-1 and siAtg5 decreased Atg5–Atg12 and LC3-II, increased natriuretic peptides, and decreased amplitude and early phase of contraction in cardiomyocytes, the latter two evaluated using ImageJ macro Myocyter recently developed by us. ET-1 further decreased cell contractility in control but not in siAtg5 cells. In conclusion, ET-1 decreased autophagy and cardiomyocyte contractility, in line with siAtg5-treated cells and the results of TAC-mice demonstrating a crucial role for autophagy in cardiomyocyte contractility and cardiac performance.

scholarly journals Microtubule-dependent distribution of mRNA in adult cardiocytes

2008 ◽  
Vol 294 (3) ◽  
pp. H1135-H1144 ◽  
Author(s):  
Dimitri Scholz ◽  
Catalin F. Baicu ◽  
William J. Tuxworth ◽  
Lin Xu ◽  
Harinath Kasiganesan ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Fluorescent Protein ◽  
Average Distance ◽  
Yellow Fluorescent Protein ◽  
Pressure Overload ◽  
Structural Protein ◽  
Protein Fusion ◽  
Microtubule Depolymerization ◽  
Microtubule Network ◽  
Hypertrophic Growth

Synthesis of myofibrillar proteins in the diffusion-restricted adult cardiocyte requires microtubule-based active transport of mRNAs as part of messenger ribonucleoprotein particles (mRNPs) to translation sites adjacent to nascent myofibrils. This is especially important for compensatory hypertrophy in response to hemodynamic overloading. The hypothesis tested here is that excessive microtubule decoration by microtubule-associated protein 4 (MAP4) after cardiac pressure overloading could disrupt mRNP transport and thus hypertrophic growth. MAP4-overexpressing and pressure-overload hypertrophied adult feline cardiocytes were infected with an adenovirus encoding zipcode-binding protein 1-enhanced yellow fluorescent protein fusion protein, which is incorporated into mRNPs, to allow imaging of these particles. Speed and distance of particle movement were measured via time-lapse microscopy. Microtubule depolymerization was used to study microtubule-based transport and distribution of mRNPs. Protein synthesis was assessed as radioautographic incorporation of [3H]phenylalanine. After microtubule depolymerization, mRNPs persist only perinuclearly and apparent mRNP production and protein synthesis decrease. Reestablishing microtubules restores mRNP production and transport as well as protein synthesis. MAP4 overdecoration of microtubules via adenovirus infection in vitro or following pressure overloading in vivo reduces the speed and average distance of mRNP movement. Thus cardiocyte microtubules are required for mRNP transport and structural protein synthesis, and MAP4 decoration of microtubules, whether directly imposed or accompanying pressure-overload hypertrophy, causes disruption of mRNP transport and protein synthesis. The dense, highly MAP4-decorated microtubule network seen in severe pressure-overload hypertrophy both may cause contractile dysfunction and, perhaps even more importantly, may prevent a fully compensatory growth response to hemodynamic overloading.

scholarly journals Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽  
2021 ◽  
Author(s):  
Yuhao Zhang ◽  
Sheng-an Su ◽  
Wudi Li ◽  
Yuankun Ma ◽  
Jian Shen ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ion Channel ◽  
Calcium Homeostasis ◽  
Pressure Overload ◽  
Cell Physiology ◽  
Hypertrophic Growth ◽  
Molecular Features ◽  
Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload

2003 ◽  
Vol 285 (3) ◽  
pp. H1261-H1269 ◽  
Author(s):  
Ping Hu ◽  
Dongfang Zhang ◽  
LeAnne Swenson ◽  
Gopa Chakrabarti ◽  
E. Dale Abel ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Insulin Signaling ◽  
Systolic Pressure ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Cardiac Response ◽  
Heart Weight ◽  
Surgical Morbidity ◽  
Aortic Banding

We developed a minimally invasive method for producing left ventricular (LV) pressure overload in mice. With the use of this technique, we quickly and reproducibly banded the transverse aorta with low surgical morbidity and mortality. Minimally invasive transverse aortic banding (MTAB) acutely and chronically increased LV systolic pressure, increased heart weight-to-body weight ratio, and induced myocardial fibrosis. We used this technique to determine whether reduced insulin signaling in the heart altered the cardiac response to pressure overload. Mice with cardiac myocyte-restricted knockout of the insulin receptor (CIRKO) have smaller hearts than wild-type (WT) controls. Four weeks after MTAB, WT and CIRKO mice had comparably increased LV systolic pressure, increased cardiac mass, and induction of mRNA for β-myosin heavy chain and atrial natriuretic factor. However, CIRKO hearts were more dilated, had depressed LV systolic function by echocardiography, and had greater interstitial fibrosis than WT mice. Expression of connective tissue growth factor was increased in banded CIRKO hearts compared with WT hearts. Thus lack of insulin signaling in the heart accelerates the transition to a more decompensated state during cardiac pressure overload. The use of the MTAB approach should facilitate the study of the pathophysiology and treatment of pressure-overload hypertrophy.

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