scholarly journals Cardiomyocyte damage control in heart failure and the role of the sarcolemma

2019 ◽  
Vol 40 (3-4) ◽  
pp. 319-333 ◽  
Author(s):  
Ashraf Kitmitto ◽  
Florence Baudoin ◽  
Elizabeth J. Cartwright
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Plasma Membrane ◽  
Cardiac Function ◽  
Structural Integrity ◽  
Damage Control ◽  
Cardiac Contraction ◽  
Membrane Injury ◽  
Cellular Processes ◽  
Repair Mechanisms

Abstract The cardiomyocyte plasma membrane, termed the sarcolemma, is fundamental for regulating a myriad of cellular processes. For example, the structural integrity of the cardiomyocyte sarcolemma is essential for mediating cardiac contraction by forming microdomains such as the t-tubular network, caveolae and the intercalated disc. Significantly, remodelling of these sarcolemma microdomains is a key feature in the development and progression of heart failure (HF). However, despite extensive characterisation of the associated molecular and ultrastructural events there is a lack of clarity surrounding the mechanisms driving adverse morphological rearrangements. The sarcolemma also provides protection, and is the cell’s first line of defence, against external stresses such as oxygen and nutrient deprivation, inflammation and oxidative stress with a loss of sarcolemma viability shown to be a key step in cell death via necrosis. Significantly, cumulative cell death is also a feature of HF, and is linked to disease progression and loss of cardiac function. Herein, we will review the link between structural and molecular remodelling of the sarcolemma associated with the progression of HF, specifically considering the evidence for: (i) Whether intrinsic, evolutionary conserved, plasma membrane injury-repair mechanisms are in operation in the heart, and (ii) if deficits in key ‘wound-healing’ proteins (annexins, dysferlin, EHD2 and MG53) may play a yet to be fully appreciated role in triggering sarcolemma microdomain remodelling and/or necrosis. Cardiomyocytes are terminally differentiated with very limited regenerative capability and therefore preserving cell viability and cardiac function is crucially important. This review presents a novel perspective on sarcolemma remodelling by considering whether targeting proteins that regulate sarcolemma injury-repair may hold promise for developing new strategies to attenuate HF progression.

vitreal cells and specialized phagocytes in the chick embryo retina: A TEM and SEM study

1990 ◽  
Vol 48 (3) ◽  
pp. 330-331
Author(s):  
M.A. Cuadros ◽  
M.J. Martinez-Guerrero ◽  
A. Rios
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Acid Phosphatase ◽  
Chick Embryo ◽  
Basement Membrane ◽  
Sem Images ◽  
Intimate Contact ◽  
Cellular Processes ◽  
Sem Study ◽  
Free Cells

In the chick embryo retina (days 3-4 of incubation), coinciding with an increase in cell death, specialized phagocytes characterized by intense acid phosphatase activity have been described. In these preparations, all free cells in the vitreal humor (vitreal cells) were strongly labeled. Conventional TEM and SEM techniques were used to characterize them and attempt to determine their relationship with retinal phagocytes.Two types of vitreal cells were distinguished. The first are located at some distance from the basement membrane of the neuroepithelium, and are rounded, with numerous vacuoles and thin cytoplasmic prolongations. Images of exo- and or endocytosis were frequent; the cells showed a well-developed Golgi apparatus (Fig. 1) In SEM images, the cells was covered with short cellular processes (Fig. 3). Cells lying parallel to or alongside the basement membrane are elongated. The plasma membrane is frequently in intimate contact with the basement membrane. These cells have generally a large cytoplasmic expansion (Fig. 5).

Abstract 15796: Increased Cardiac Heme Levels Through Cardiac Overexpression of Delta-aminolevulinic Acid Synthase 2 (ALAS2) Lead to Exacerbated Ischemic Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Konrad T Sawicki ◽  
Meng Shang ◽  
Rongxue Wu ◽  
Hsiang-Chun Chang ◽  
Arineh Khechaduri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cell Death ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Ischemic Cardiomyopathy ◽  
Aminolevulinic Acid ◽  
Causative Role ◽  
Mitochondrial Oxidative Stress ◽  
Coronary Ligation

Introduction: Heme is an essential iron-containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate-limiting enzyme in heme synthesis, δ-aminolevulinic acid synthase 2 (ALAS2), which is normally not expressed in cardiomyocytes. Hypothesis: We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS2) leads to increased oxidative stress and cell death in the heart. Results: We first showed that ALAS2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac-specific overexpression of ALAS2. While ALAS2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to non-transgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death by ALAS2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of ALAS2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to ALAS2-overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased ALAS2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased ALAS2 induction and heme accumulation in failing human hearts from patients with ischemic cardiomyopathy compared to non-ischemic cardiomyopathy. Conclusions: Heme accumulation is detrimental to cardiac function under ischemic conditions, and reducing heme in the heart may be a novel approach for protection against the development of heart failure.

Abstract 268: Differential Activation and Subcellular Targeting of Erk1/2 and Akt in Response to β-Adrenergic Receptor-Mediated Transactivation of Epidermal Growth Factor Receptor in Cardiomyocytes

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Laurel A Grisanti ◽  
Jennifer A Talarico ◽  
Rhonda C Carter ◽  
Scott W Radcliffe ◽  
Douglas G Tilley
Keyword(s):  
Heart Failure ◽  
Plasma Membrane ◽  
Cardiac Function ◽  
Growth Factor Receptor ◽  
Subcellular Targeting ◽  
Egfr Transactivation ◽  
Differential Activation ◽  
Akt Phosphorylation ◽  
Egfr Inhibition ◽  
Pi3k Activity

β-adrenergic receptors (βAR) are critical regulators of cardiac function whose dysregulation during heart failure are associated with diminished cardiac function, however βAR-mediated EGFR transactivation has been shown to relay cardioprotection via unknown mechanisms. We hypothesized that EGFR transactivation may result in differential activation and subcellular targeting of prosurvival kinases known to be downstream of EGFR, namely ERK1/2 and Akt. Thus, ERK1/2 and Akt phosphorylation and subcellular distribution was assessed in rat neonatal cardiomyocytes (RNCM). Treatment of RNCM with the βAR agonist isoproterenol (Iso) resulted in significant phosphorylation of both ERK1/2 (P-ERK) and Akt (P-Akt), in the cytosolic, plasma membrane and nuclear fractions. EGFR inhibition with AG1478 resulted in complete ablation of Iso-induced P-ERK in all fractions, as did MEK1/2 inhibition with PD184352. Total ERK levels did not change in any fraction under any condition, which along with the PD184352 data suggests Iso-mediated EGFR-dependent effects on ERK1/2 activity at different cellular locations is reliant upon MEK1/2 trafficking. While Akt phosphorylation in response to Iso-mediated EGFR transactivation was not sensitive to EGFR inhibition in the cytosol, the P-Akt response was completely abrogated by AG1478 in the plasma membrane and nuclear fractions. The PI3K inhibitor LY-294002 blocked Iso-induced Akt phosphorylation in all fractions, confirming reliance upon PI3K activity for Iso-mediated Akt activation. Additionally, total Akt levels remained constant over all treatments except at the plasma membrane, where AG 1478 reduced T-Akt, suggesting that Akt recruitment and PI3K activity each contribute to an increase in plasma membrane-associated P-Akt, whereas increased nuclear P-Akt in response to Iso-induced EGFR signaling depends solely on PI3K activity. In all, these results demonstrate differential impact of βAR-mediated EGFR transactivation on the subcellular activation and targeting of cardiomyocyte ERK1/2 and Akt. Further understanding of the downstream consequences of these effects in response to βAR-mediated EGFR transactivation could lead to improved therapies for the treatment of heart failure.

Ion channnels and transporters in cancer. 5. Ion channels in control of cancer and cell apoptosis

2011 ◽  
Vol 301 (6) ◽  
pp. C1281-C1289 ◽  
Author(s):  
V'yacheslav Lehen'kyi ◽  
George Shapovalov ◽  
Roman Skryma ◽  
Natalia Prevarskaya
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Plasma Membrane ◽  
Ion Channels ◽  
Programmed Cell Death ◽  
Tissue Homeostasis ◽  
Death Rates ◽  
Cellular Processes ◽  
Regulation Of Cell Cycle

Ion channels contribute to virtually all basic cellular processes, including such crucial ones for maintaining tissue homeostasis as proliferation, differentiation, and apoptosis. The involvement of ion channels in regulation of programmed cell death, or apoptosis, has been known for at least three decades based on observation that classical blockers of ion channels can influence cell death rates, prolonging or shortening cell survival. Identification of the central role of these channels in regulation of cell cycle and apoptosis as well as the recent discovery that the expression of ion channels is not limited solely to the plasma membrane, but may also include membranes of internal compartments, has led researchers to appreciate the pivotal role of ion channels plays in development of cancer. This review focuses on the aspects of programmed cell death influenced by various ion channels and how dysfunctions and misregulations of these channels may affect the development and progression of different cancers.

Relationship between cardiomyocyte cell death and cardiac function during hypertensive cardiac remodelling in Dahl rats

2002 ◽  
Vol 102 (3) ◽  
pp. 329-335 ◽  
Author(s):  
Shuntaro IKEDA ◽  
Mareomi HAMADA ◽  
Peng QU ◽  
Go HIASA ◽  
Hidetoshi HASHIDA ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cardiac Function ◽  
Apoptotic Cell ◽  
Mrna Level ◽  
Northern Blotting ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Terminal Deoxynucleotidyl Transferase

The exact mechanisms responsible for the progression of heart failure remain unclear. We investigated the in vivo relationship between the incidence of apoptotic cell death and left ventricular function serially from the beginning of hypertension to decompensated heart failure in Dahl salt-sensitive rats. Dahl salt-resistant and Dahl salt-sensitive rats were fed on a high-salt diet from 6 weeks of age. Systolic blood pressure was recorded by the tail-cuff method every week. Cardiac function in vivo was evaluated by echocardiography and cardiac catheterization. Cardiomyocyte apoptosis was detected by the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) method. The gene expression of Bax, Bcl-2 and Bcl-xL was analysed by Northern blotting. The TUNEL method revealed that the incidence of cardiomyocyte apoptosis was significantly increased in the hearts of 18-week-old Dahl salt-sensitive rats (apoptotic index 1.3±0.1%). Northern blot analysis revealed that the Bcl-xL mRNA level increased gradually during the progression towards heart failure. In conclusion, these data suggest that cardiomyocyte apoptosis is a terminal event, and plays a role as an aggravating factor in the vicious cycle of heart failure.

Abstract 2892: Inhibition of Toll-like Receptor-2 May Limit Cardiac Dysfunction After a Myocardial Infarction by Reducing Apoptosis via a p38 MAPK-dependent Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Brenda B Su ◽  
Zhuo Sun ◽  
Hiroko Fujii ◽  
Jun Wu ◽  
Zhihong Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Cardiac Function ◽  
P38 Mapk ◽  
Cytokine Production ◽  
Infarct Region ◽  
Tnf Α ◽  
Infarcted Region

Background: Inhibition of toll-like receptors (TLRs) may be a new treatment to prevent congestive heart failure during post-myocardial infarction (MI) surgical interventions. TLR2 knockout (KO) mice provide an opportunity to predict the effects of inhibitors and to establish the mechanisms responsible for their beneficial effects. This study was performed to establish the pathways responsible for myocardial protection in the absence of TLRs after MI. Methods and Results: In vivo study: MI was induced in TLR2 KO and wild-type (WT) C56B/6J mice by anterior coronary artery ligation. Cardiac function was preserved in the KO mice compared to the WT mice (echocardiography demonstrated higher fractional shortening and fractional area change, p<0.05) at 3, 7 and 28 days after the MI. To evaluate the mechanisms responsible for the functional improvements, cardiac cytokine production was measured. TNF-α, IL-1β and IL-6 were significantly decreased in the infarct region of KO compared to WT mice at 3 days post-MI. On day 7, IL-6 production was significantly decreased in the infarct region and TNF-α was decreased in the non-infarcted region of KO compared to WT mice. Phosphorylation of p38 MAPK was prevented, and the number of TUNEL positive nuclei was reduced in the infarct region of KO compared to WT mice. Phosphorylation of Akt was upregulated in the non-infarcted region of KO mice at 3 days after MI. There were no differences in the phosphorylation of ERK or JNK at the same time point. In vitro study: Myocardial fibroblasts were isolated from KO and WT mice, cultured, and then exposed to hydrogen peroxide. Compared to cells from WT mice, cells from KO mice exhibited greater protection (less cell death) and reduced p38 phosphorylation as early as 5 and 15 minutes after hydrogen peroxide stimulation. Conclusions: TLR2 KO mice allow the assessment of the potential benefits of TLR inhibitors. Reducing TLR2 after an infarction will decrease cytokine production and cell death in a p38 MAPK-dependent manner, which in turn will contribute to the preservation of cardiac function. Early inhibition of TLR2 function may represent a new target to prevent heart failure after MI.

scholarly journals Restructuring of the plasma membrane upon damage by LC3-associated macropinocytosis

2021 ◽  
Vol 7 (27) ◽  
pp. eabg1969
Author(s):  
Stine Lauritzen Sønder ◽  
Swantje Christin Häger ◽  
Anne Sofie Busk Heitmann ◽  
Lisa B. Frankel ◽  
Catarina Dias ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Integrity ◽  
Eukaryotic Cell ◽  
Membrane Injury ◽  
Repair Site ◽  
Damaged Material ◽  
Cell Life ◽  
Repair Mechanisms ◽  
Membrane Resealing

The plasma membrane shapes and protects the eukaryotic cell from its surroundings and is crucial for cell life. Although initial repair mechanisms to reseal injured membranes are well established, less is known about how cells restructure damaged membranes in the aftermath to restore homeostasis. Here, we show that cells respond to plasma membrane injury by activating proteins associated with macropinocytosis specifically at the damaged membrane. Subsequent to membrane resealing, cells form large macropinosomes originating from the repair site, which eventually become positive for autophagy-related LC3B protein. This process occurs independent of ULK1, ATG13, and WIPI2 but dependent on ATG7, p62, and Rubicon. Internalized macropinosomes shrink in the cytoplasm, likely by osmotic draining, and eventually fuse with lysosomes. We propose that a form of macropinocytosis coupled to noncanonical autophagy, which we term LC3-associated macropinocytosis (LAM) functions to remove damaged material from the plasma membrane and restore membrane integrity upon injury.

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