Upregulation of GRP78 and caspase-12 in diastolic failing heart.

2008 ◽  
Vol 55 (3) ◽  
pp. 511-516 ◽  
Author(s):  
Yingying Sun ◽  
Guanghui Liu ◽  
Tao Song ◽  
Fang Liu ◽  
Weiqiang Kang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Diastolic Heart Failure ◽  
Critical Role ◽  
Mrna Levels ◽  
Apoptotic Pathway ◽  
Spontaneously Hypertensive ◽  
Caspase 12 ◽  
Apoptosis Pathways ◽  
Cardiac Myocyte Apoptosis

The endoplasmic reticulum (ER) fulfills multiple cellular functions. Various stimuli can potentially cause ER stress (ERS). ERS is one of the intrinsic apoptosis pathways and apoptosis plays a critical role in hypertension. Glucose regulated protein 78 (GRP78) has been widely used as a marker for ERS and caspase-12 mediated apoptosis was a specific apoptotic pathway of ER. The expression of GRP78 and caspase-12 remains poorly understood in the diastolic heart failure resulting from hypertension. We used spontaneously hypertensive rats (SHRs) to establish a model of diastolic heart failure, and performed immunohistochemistry, western blot, and real-time PCR to analyze GRP78 and caspase-12. We found that GRP78 and caspase-12 had enhanced expression at protein and mRNA levels. These results suggest that GRP78 and caspase-12 were upregulated in cardiomyocytes and ERS can contribute to cardiac myocyte apoptosis in the diastolic heart failure resulting from hypertension.

scholarly journals A mechanistic role for cardiac myocyte apoptosis in heart failure

2003 ◽  
Vol 111 (10) ◽  
pp. 1497-1504 ◽  
Author(s):  
Detlef Wencker ◽  
Madhulika Chandra ◽  
Khanh Nguyen ◽  
Wenfeng Miao ◽  
Stavros Garantziotis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis

HSP60 in heart failure: abnormal distribution and role in cardiac myocyte apoptosis

2007 ◽  
Vol 293 (4) ◽  
pp. H2238-H2247 ◽  
Author(s):  
Li Lin ◽  
S. C. Kim ◽  
Yin Wang ◽  
S. Gupta ◽  
B. Davis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Plasma Membrane ◽  
Cell Surface ◽  
Cardiac Myocyte ◽  
Cardiac Injury ◽  
Acute Injury ◽  
Tnf Α ◽  
Inflammatory State ◽  
Cardiac Myocyte Apoptosis ◽  
End Stage

Heat shock protein (HSP) 60 is a mitochondrial and cytosolic protein. Previously, we reported that HSP60 doubled in end-stage heart failure, even though levels of the protective HSP72 were unchanged. Furthermore, we observed that acute injury in adult cardiac myocytes resulted in movement of HSP60 to the plasma membrane. We hypothesized that the inflammatory state of heart failure would cause translocation of HSP60 to the plasma membrane and that this would provide a pathway for cardiac injury. Two models were used to test this hypothesis: 1) a rat model of heart failure and 2) human explanted failing hearts. We found that HSP60 localized to the plasma membrane and was also found in the plasma early in heart failure. Plasma membrane HSP60 localized to lipid rafts and was detectable on the cell surface with the use of both flow cytometry and confocal microscopy. Localization of HSP60 to the cell surface correlated with increased apoptosis. In heart failure, HSP60 is in the plasma membrane fraction, on the cell surface, and in the plasma. Membrane HSP60 correlated with increased apoptosis. Release of HSP60 may activate the innate immune system, promoting a proinflammatory state, including an increase in TNF-α. Thus abnormal trafficking of HSP60 to the cell surface may be an early trigger for myocyte loss and the progression of heart failure.

scholarly journals Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease

2020 ◽  
Vol 134 (19) ◽  
pp. 2623-2643
Author(s):  
Andrew Geissler ◽  
Sergey Ryzhov ◽  
Douglas B. Sawyer
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Tyrosine Kinases ◽  
Cardiac Myocyte ◽  
Diastolic Heart Failure ◽  
Systolic Heart Failure ◽  
Circulatory System ◽  
Cardiovascular Responses ◽  
Adaptive Responses ◽  
Beneficial Effects

Abstract Neuregulins (NRGs) are protein ligands that act through ErbB receptor tyrosine kinases to regulate tissue morphogenesis, plasticity, and adaptive responses to physiologic needs in multiple tissues, including the heart and circulatory system. The role of NRG/ErbB signaling in cardiovascular biology, and how it responds to physiologic and pathologic stresses is a rapidly evolving field. While initial concepts focused on the role that NRG may play in regulating cardiac myocyte responses, including cell survival, growth, adaptation to stress, and proliferation, emerging data support a broader role for NRGs in the regulation of metabolism, inflammation, and fibrosis in response to injury. The constellation of effects modulated by NRGs may account for the findings that two distinct forms of recombinant NRG-1 have beneficial effects on cardiac function in humans with systolic heart failure. NRG-4 has recently emerged as an adipokine with similar potential to regulate cardiovascular responses to inflammation and injury. Beyond systolic heart failure, NRGs appear to have beneficial effects in diastolic heart failure, prevention of atherosclerosis, preventing adverse effects on diabetes on the heart and vasculature, including atherosclerosis, as well as the cardiac dysfunction associated with sepsis. Collectively, this literature supports the further examination of how this developmentally critical signaling system functions and how it might be leveraged to treat cardiovascular disease.

Abstract 105: Maternal Diet Leads to Nephron Count Differences After Postnatal Day 14 and Time-dependent Differences in Apoptosis and Unfolded Protein Response in Dahl Salt-sensitive Rats

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Erwin T Cabacungan ◽  
Aron M Geurts ◽  
David L Mattson ◽  
Liang Mingyu
Keyword(s):  
Protein Expression ◽  
Unfolded Protein Response ◽  
Time Dependent ◽  
Mrna Levels ◽  
Related Protein ◽  
Apoptotic Pathway ◽  
Time Points ◽  
Unfolded Protein ◽  
Caspase 12 ◽  
Protein Response

We have shown that maternal exposure to Casein-based AIN-76A diet [SS/JrHsdMcwi (SS/Mcw) rats] compared to grain-based 5L2F diet [SS/JrHsdMcwiCrl (SS/Crl) rats] during the gestational-lactational period exacerbates the development of salt-induced hypertension and renal injury in adult SS rats. We hypothesized that SS/Mcw rats will have significantly fewer glomeruli than SS/Crl rats, and determined its potential mechanisms. At different time points during development [embryonic day 20 (E 20), day of life (DOL) 14, 21, 56]: glomerular counts were determined by maceration method and by glomerular density (total glomerular number/renal cortex area); apoptosis was measured by TUNEL assay; RT-PCR, Western Blot and immunostaining were used to examine the expression level of genes involved in the apoptotic pathway and unfolded protein response (UPR). We found lower glomerular counts in SS/Mcw compared to SS/Crl rats at DOL 21 [26048±1423 per kidney vs. 34766±1821 (p<0.001] and DOL 56 [15717±2052 vs. 27999±3362 (p <0.001)], and lower glomerular densities [DOL 21, 10.8±1.0/mm2 vs. 13.2±1.6 (p<0.001); DOL 56, 2.4±0.1 vs. 3.6±0.2 (p < 0.001)]. Glomerular density was not different between SS/Mcw and SS/Crl at DOL 14 when nephrogenesis is complete. We found higher glomerular apoptosis in SS/Mcw compared to SS/Crl rats at DOL 14 [9.5±1.4 per 100 glomeruli vs. 5.1±1.8 (p<0.01)] and DOL 21 [5.2±0.7 vs. 3.6±0.5 (p <0.01)]. mRNA levels of several genes involved in intrinsic apoptotic pathway and UPR were significantly upregulated in SS/Mcw rats compared to SS/Crl rats at different time points. Significantly lower UPR-related protein expression in SS/Mcw compared to SS/Crl rats was detected for JNK and GRP78 (DOL 14 and 56) and CHOP (DOL 56). Significantly higher UPR-related protein expression in SS/Mcw compared to SS/Crl rats were detected for GRP78 (E 20), JNK (DOL 21) and Caspase 12 (DOL 14, 21 and 56). Caspase 12 was located in the glomeruli in DOL 21 and 56 kidneys. Our results show marked decrease of glomerular counts with age in SS/Mcw compared to SS/Crl after DOL 14. The time-dependent differences in the expression of apoptosis and UPR-related genes leading to glomerular apoptosis may be a potential mechanism for the nephron count differences between SS/Mcw and SS/Crl.

Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat

1997 ◽  
Vol 272 (5) ◽  
pp. H2313-H2319 ◽  
Author(s):  
Z. Li ◽  
O. H. Bing ◽  
X. Long ◽  
K. G. Robinson ◽  
E. G. Lakatta
Keyword(s):  
Heart Failure ◽  
Angiotensin Converting Enzyme ◽  
Angiotensin Converting Enzyme Inhibitor ◽  
Enzyme Inhibitor ◽  
Apoptotic Cells ◽  
Mrna Levels ◽  
Converting Enzyme ◽  
Spontaneously Hypertensive ◽  
Converting Enzyme Inhibitor ◽  
Significant Difference

The transition from compensated hypertrophy to failure in spontaneously hypertensive rats (SHR) of advanced age is associated with a marked increase in collagen, a reduction in myocyte mass, and a reduction in maximum Ca(2+)-activated myofibrillar force. We hypothesized that the reduction in myocyte mass and associated functional loss may be due to increased cell death by apoptosis. To test this hypothesis, we studied hearts from failing (SHR-F) and nonfailing SHR (SHR-NF) and age-matched Wistar-Kyoto rats (WKY). In addition, hearts from SHR-F that had been treated with an angiotensin-converting enzyme inhibitor (captopril) for an average of 27 days were also studied. Apoptotic cells were quantified in cross sections of myocardium by the terminal deoxynucleotidyltransferase- mediated 2'-deoxyuridine 5'-triphosphate nick end labeling technique. To identify the type of the cells undergoing apoptosis, sections were also stained for alpha-sarcomeric actin. Apoptotic cells were significantly increased in the SHR-F (38.92 +/- 12.79 vs. 8.05 +/- 3.98 cells/100,000 nuclei in SHR-NF; P < 0.05 and vs. 2.21 +/- 1.4 cells/100,000 nuclei in WKY; P < 0.01). Captopril treatment of SHR-F reduced the number of apoptotic cells to the level in SHR-NF (9.17 +/- 1.53 cells/100,000 nuclei; P < 0.01 vs. SHR-F). Most apoptotic cells were of cardiac myocyte origin. There was no significant difference in Bcl-2 protein expressed by hearts among the three groups. WAF-1 mRNA levels were increased in both SHR groups vs. WKY; in SHR-F, the density of WAF-1 mRNA was higher than in SHR-NF. Thus increased numbers of apoptotic cells are present in failing SHR hearts, suggesting that apoptosis might be a mechanism involved in the reduction of myocyte mass that accompanies the transition from stable compensation to heart failure in this model. Administration of the angiotensin-converting enzyme inhibitor captopril, which ameliorates heart failure in this model, is associated with a reduction in the exaggerated apoptosis that accompanies heart failure.

scholarly journals Ginkgo biloba Leaf Extract Protects against Myocardial Injury via Attenuation of Endoplasmic Reticulum Stress in Streptozotocin-Induced Diabetic ApoE−/− Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Jinfan Tian ◽  
Yanfei Liu ◽  
Yue Liu ◽  
Keji Chen ◽  
Shuzheng Lyu
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Myocardial Injury ◽  
Caspase 3 ◽  
Interstitial Fibrosis ◽  
Serum Levels ◽  
Cardiomyocyte Apoptosis ◽  
Mrna Levels ◽  
Caspase 12 ◽  
Apoptosis Pathways

Diabetes was induced in high-fat diet-fed ApoE−/− mice via administration of low-dose streptozotocin (STZ) for five days. Mice were then treated with GBE (200 or 400 mg/kg) by gastric gavage daily for 12 weeks. Mice in the untreated diabetic group received saline instead, and nondiabetic C57BL/6J mice served as controls. Collagen І and ІІІ mRNA expression was measured by real-time PCR. TNF-α, IL-1β mRNA levels, and NF-κB expression were determined to analyze intramyocardial inflammation. Hallmarks of endoplasmic reticulum stress- (ERS-) related apoptosis pathways, including phosphorylated c-Jun N-terminal kinase (p-JNK), C/EBP homologous protein (CHOP), caspase-12, and cleaved caspase-3, were analyzed by Western blotting. Diabetic ApoE−/− myocardial injury was associated with increased cardiomyocyte apoptosis (increased expression of p-JNK, CHOP, caspase-12, and cleaved caspase-3), interstitial fibrosis (increased mRNA levels of collagen І and ІІІ), and inflammation (increased mRNA levels of TNF-α and IL-1β, and NF-κB expression). GBE at 200 and 400 mg/kg/day significantly attenuated cardiomyocyte apoptosis, collagen deposition, and inflammation in diabetic mice via inhibition of the p-JNK, CHOP, and caspase-12 pathways. Serum levels of the proinflammatory cytokines (IL-6, IL-1β, and TNF-α), blood glucose, and lipid profiles were also regulated by GBE treatment. GBE might be beneficial in the treatment of diabetic myocardial injury.

scholarly journals Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI

2008 ◽  
Vol 294 (6) ◽  
pp. H2604-H2613 ◽  
Author(s):  
Jianfeng Du ◽  
Jing Liu ◽  
Han-Zhong Feng ◽  
M. M. Hossain ◽  
Nariman Gobara ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Troponin I ◽  
Negative Impact ◽  
Diastolic Heart Failure ◽  
Critical Role ◽  
Restrictive Cardiomyopathy ◽  
Contraction And Relaxation

Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart (cTnI193His mice). The objective of this study was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function and pathophysiological changes were monitored in cTnI193His mice and wild-type littermates for a period of 12 mo. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with high-resolution echocardiography by a reversed E-to-A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. At the age of 12 mo, cardiac output in cTnI193His mice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI193His on ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI193His myocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve CO. The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricles and functionally by diastolic dysfunction and diastolic heart failure. The results demonstrate a critical role of the COOH-terminal domain of cTnI in the diastolic function of cardiac muscle.

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