Abstract 263: Defective Autophagy Plays a Role in the Development of Angiotensin-Induced Cardiac Hypertrophy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Simon C Johnson ◽  
Vy Nguyen ◽  
Anthony Castanza ◽  
Peter S Rabinovitch
Keyword(s):  
Cell Death ◽  
Cardiac Hypertrophy ◽  
Ex Vivo ◽  
Genetic Diseases ◽  
Pressure Overload ◽  
Small Population ◽  
Tissue Imaging ◽  
Unit Structure ◽  
Tissue Degeneration ◽  
Cell Organization

While activated autophagy is a well reported feature of cardiac disease, the exact role of autophagy in the etiology and progression of cardiac hypertrophy and dysfunction is unclear; activation of autophagy appears to play either pro-survival or pro-apoptotic functions depending on the context. Here we demonstrate that dysfunctional autophagy plays a role in the development of angiotensin II-induced cardiac hypertrophy. Using a live, ex-vivo tissue imaging technique and transgenic LC3-GFP expressing mice we found that after short term (1 week) treatment, autophagic markers accumulate in angiotensin treated mouse hearts and that in a small population of cells this accumulation reaches a critical level where normal cell organization, specifically mitochondrial localization and contractile unit structure, and tissue architecture are disrupted. These observations are reminiscent of genetic diseases associated with dysfunctional autophagy, such as inclusion body myositis, where autophagic vesicles fail to properly clear and lead to cell death and tissue degeneration. We suggest that failed autophagy contributes to pressure-overload induced hypertrophy and that the cell death associated with dramatically dysfunctional autophagy in a subset of cardiomyocytes precedes fibrosis. This work provides a clear role for dysfunctional autophagy in promoting hypertrophy and fibrosis, and supports the notion that the promotion of successful autophagy is a clinically relevant target for therapeutic intervention.

scholarly journals In vivo administration of calpeptin attenuates calpain activation and cardiomyocyte loss in pressure-overloaded feline myocardium

2008 ◽  
Vol 295 (1) ◽  
pp. H314-H326 ◽  
Author(s):  
Santhosh K. Mani ◽  
Hirokazu Shiraishi ◽  
Sundaravadivel Balasubramanian ◽  
Kentaro Yamane ◽  
Meenakshi Chellaiah ◽  
...  
Keyword(s):  
Cell Death ◽  
Cardiac Hypertrophy ◽  
Caspase 3 ◽  
Pressure Overload ◽  
Cytoskeletal Proteins ◽  
Tunel Staining ◽  
Histone H2b ◽  
Calpain Activation ◽  
Calpain Inhibition

Calpain activation is linked to the cleavage of several cytoskeletal proteins and could be an important contributor to the loss of cardiomyocytes and contractile dysfunction during cardiac pressure overload (PO). Using a feline right ventricular (RV) PO model, we analyzed calpain activation during the early compensatory period of cardiac hypertrophy. Calpain enrichment and its increased activity with a reduced calpastatin level were observed in 24- to 48-h-PO myocardium, and these changes returned to basal level by 1 wk of PO. Histochemical studies in 24-h-PO myocardium revealed the presence of TdT-mediated dUTP nick-end label (TUNEL)-positive cardiomyocytes, which exhibited enrichment of calpain and gelsolin. Biochemical studies showed an increase in histone H2B phosphorylation and cytoskeletal binding and cleavage of gelsolin, which indicate programmed cardiomyocyte cell death. To test whether calpain inhibition could prevent these changes, we administered calpeptin (0.6 mg/kg iv) by bolus injections twice, 15 min before and 6 h after induction of 24-h PO. Calpeptin blocked the following PO-induced changes: calpain enrichment and activation, decreased calpastatin level, caspase-3 activation, enrichment and cleavage of gelsolin, TUNEL staining, and histone H2B phosphorylation. Although similar administration of a caspase inhibitor, N-benzoylcarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VD-fmk), blocked caspase-3 activation, it did not alleviate other aforementioned changes. These results indicate that biochemical markers of cardiomyocyte cell death, such as sarcomeric disarray, gelsolin cleavage, and TUNEL-positive nuclei, are mediated, at least in part, by calpain and that calpeptin may serve as a potential therapeutic agent to prevent cardiomyocyte loss and preserve myocardial structure and function during cardiac hypertrophy.

Cardiomyocyte-restricted inhibition of G protein-coupled receptor kinase-3 attenuates cardiac dysfunction after chronic pressure overload

2012 ◽  
Vol 303 (1) ◽  
pp. H66-H74 ◽  
Author(s):  
Thomas G. von Lueder ◽  
Jørgen Gravning ◽  
Ole-Jakob How ◽  
Leif E. Vinge ◽  
Mohammed Shakil Ahmed ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
G Protein ◽  
Cardiac Dysfunction ◽  
Adrenergic Receptor ◽  
Ex Vivo ◽  
Pressure Overload ◽  
Cardiac Mass ◽  
Receptor Kinase ◽  
Volume Analysis ◽  
G Protein Coupled

Transgenic mice with cardiac-specific expression of a peptide inhibitor of G protein-coupled receptor kinase (GRK)3 [transgenic COOH-terminal GRK3 (GRK3ct) mice] display myocardial hypercontractility without hypertrophy and enhanced α1-adrenergic receptor signaling. A role for GRK3 in the pathogenesis of heart failure (HF) has not been investigated, but inhibition of its isozyme, GRK2, has been beneficial in several HF models. Here, we tested whether inhibition of GRK3 modulated evolving cardiac hypertrophy and dysfunction after pressure overload. Weight-matched male GRK3ct transgenic and nontransgenic littermate control (NLC) mice subjected to chronic pressure overload by abdominal aortic banding (AB) were compared with sham-operated (SH) mice. At 6 wk after AB, a significant increase of cardiac mass consistent with induction of hypertrophy was found, but no differences between GRK3ct-AB and NLC-AB mice were discerned. Simultaneous left ventricular (LV) pressure-volume analysis of electrically paced, ex vivo perfused working hearts revealed substantially reduced systolic and diastolic function in NLC-AB mice ( n = 7), which was completely preserved in GRK3ct-AB mice ( n = 7). An additional cohort was subjected to in vivo cardiac catheterization and LV pressure-volume analysis at 12 wk after AB. NLC-AB mice ( n = 11) displayed elevated end-diastolic pressure (8.5 ± 3.1 vs. 2.9 ± 1.2 mmHg, P < 0.05), reduced cardiac output (3,448 ± 323 vs. 4,488 ± 342 μl/min, P < 0.05), and reduced dP/d tmax and dP/d tmin (both P < 0.05) compared with GRK3ct-AB mice ( n = 16), corroborating the preserved cardiac structure and function observed in GRK3ct-AB hearts assessed ex vivo. Increased cardiac mass and myocardial mRNA expression of β-myosin heavy chain confirmed the similar induction of cardiac hypertrophy in both AB groups, but only NLC-AB hearts displayed significantly elevated mRNA levels of brain natriuretic peptide and myocardial collagen contents as well as reduced β1-adrenergic receptor responsiveness to isoproterenol, indicating increased LV wall stress and the transition to HF. Inhibition of cardiac GRK3 in mice does not alter the hypertrophic response but attenuates cardiac dysfunction and HF after chronic pressure overload.

Abstract 074: GRK5 Increases Cardiac NFAT Transcriptional Activity

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Jonathan Hullmann ◽  
J K Chuprun ◽  
Erhe Gao ◽  
Walter J Koch
Keyword(s):  
Cardiac Hypertrophy ◽  
Ex Vivo ◽  
Pressure Overload ◽  
Luciferase Reporter ◽  
Wild Type ◽  
Activated T Cells ◽  
Reporter Mice ◽  
Nuclear Dependence ◽  
Independent Effects

Introduction: G protein-coupled receptor (GPCR) kinase-2 and -5 (GRK2 and GRK5) have been shown to be up-regulated in failing human myocardium. While the canonical role of GRKs is to desensitize receptors via phosphorylation, it has been shown that GRK5, unlike GRK2, can reside in the nucleus of cardiomyocytes and exert GPCR-independent effects that promote maladaptive cardiac hypertrophy and heart failure (HF). Previously, our lab has shown that GRK5 increases hypertrophic gene transcription through the phosphorylation of histone deacetylase 5 (HDAC5) and subsequent disinhibition of the transcription factor, myocyte enhancer factor-2 (MEF2). Use of GRK5 knockout (KO) mice has recently proved that GRK5 is indeed a physiological HDAC kinase during hypertrophic stress. Through experiments described below we have now identified the nuclear factor of activated T cells (NFAT) pathway as another potential target of GRK5 during cardiac hypertrophy that may play a role in its facilitation of HF. Methods and Results: Cardiac-specific NFAT-luciferase reporter mice were crossed with mice that overexpress wild-type GRK5 in myocytes to determine the role for GRK5 in NFAT signaling. These double-transgenic mice along with controls were stressed using the hypertrophic α 1 -adrenergic agonist phenylephrine (PE) as well as ventricular pressure-overload via transverse aortic constriction (TAC). NFAT activity was determined by both in vivo and ex vivo luciferase assays as well as RT-PCR for the NFAT target gene RCAN. Cardiac specific GRK5 overexpression leads to an increase in NFAT activity in the basal state as well as after both forms of hypertrophic stress. This was reproduced in cultured myocytes using a NFAT-reporter construct. Overexpression of a mutant GRK5 that cannot enter the nucleus appears to not activate NFAT demonstrating a nuclear-dependence. Consistent with this, GRK5 KO mice after TAC showed a decrease in the up-regulation of RCAN transcription as compared to wild-type mice. Studies are ongoing to determine the mechanism of GRK5’s regulation of cardiac NFAT activity. Conclusions: This study provides another non-canonical role for GRK5 in activating the hypertrophic NFAT pathway in cardiomyocytes.

scholarly journals Changes in T-Tubules and Sarcoplasmic Reticulum in Ventricular Myocytes in Early Cardiac Hypertrophy in a Pressure Overload Rat Model

2015 ◽  
Vol 37 (4) ◽  
pp. 1329-1344 ◽  
Author(s):  
Perla Pérez-Treviño ◽  
Jorge Pérez-Treviño ◽  
Cuauhtémoc Borja-Villa ◽  
Noemí García ◽  
Julio Altamirano
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Structural Changes ◽  
Ventricular Myocytes ◽  
Ex Vivo ◽  
Pressure Overload ◽  
Cardiac Performance ◽  
Adrenergic Stimulation ◽  
Abdominal Aortic ◽  
Functional Remodeling

Background/Aims: Pressure-overload (PO) causes cardiac hypertrophy (CH), and eventually leads to heart failure (HF). HF ventricular myocytes present transverse-tubules (TT) loss or disarrangement and decreased sarcoplasmic reticulum (SR) density, and both contribute to altered Ca2+ signaling and heart dysfunction. It has been shown that TT remodeling precedes HF, however, it is unknown whether SR structural and functional remodeling also starts early in CH. Methods: Using confocal microscopy, we assessed TT (with Di-8-ANNEPS) and SR (with SR-trapped Mag-Fluo-4) densities, as well as SR fluorophore diffusion (fluorescence recovery after photobleach; FRAP), cytosolic Ca2+ signaling and ex vivo cardiac performance in a PO rat hypertrophy model induced by abdominal aortic constriction (at 6 weeks). Results: Rats developed CH, while cardiac performance, basal and upon β-adrenergic stimulation, remained unaltered. TT density decreased by ∼14%, without spatial disarrangement, while SR density decreased by ∼7%. More important, FRAP was ∼30% slower, but with similar maximum recovery, suggesting decreased SR interconnectivity. Systolic and diastolic Ca2+ signaling and SR Ca2+ content were unaltered. Conclusion: SR remodeling is an early CH event, similar to TT remodeling, appearing during compensated hypertrophy. Nevertheless, myocytes can withstand those moderate structural changes in SR and TT, preserving normal Ca2+ signaling and contractility.

Pinoresinol diglucoside (PDG) attenuates cardiac hypertrophy via AKT/mTOR/NF-κB signaling in pressure overload-induced rats

2021 ◽  
Vol 272 ◽  
pp. 113920
Author(s):  
Yusha Chen ◽  
Ruiyan Pan ◽  
Juanjuan Zhang ◽  
Tianming Liang ◽  
Juan Guo ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Pinoresinol Diglucoside

scholarly journals Moderately Inducing Autophagy Reduces Tertiary Brain Injury after Perinatal Hypoxia-Ischemia

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 898
Author(s):  
Brian H. Kim ◽  
Maciej Jeziorek ◽  
Hur Dolunay Kanal ◽  
Viorica Raluca Contu ◽  
Radek Dobrowolski ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Integrity ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Structures ◽  
Improved Outcomes ◽  
Hypoxia Ischemia ◽  
Tgfβ Receptor ◽  
Progressive Neurodegeneration

Recent studies of cerebral hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)β1 is highly elevated following HI and that delivering an antagonist for TGFβ receptor activin-like kinase 5 (ALK5)—SB505124—three days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated light chain 3 (LC3), a key protein known to mediate autophagy. However, those studies did not determine whether (1) SB was acting directly on the CNS and (2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist three days after HI reduced actively apoptotic cells by ~90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting three days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

scholarly journals TMEM173 protects against pressure overload‐induced cardiac hypertrophy by modulating autophagy

2020 ◽  
Author(s):  
Ya‐Ge Jin ◽  
Heng Zhou ◽  
Di Fan ◽  
Yan Che ◽  
Zhao‐Peng Wang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload
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