PYRROLIDINE DITHIOCARBAMATE ACTIVATES THE HEAT SHOCK RESPONSE AND THEREBY INDUCES APOPTOSIS IN PRIMED ENDOTHELIAL CELLS

The heat shock response is an important cytoprotective mechanism for protein homeostasis and is an essential protective response to cellular stress and injury. Studies on changes in the heat shock response with aging have been mixed with regard to whether it is inhibited, and this, at least in part, reflects different tissues and different models. Cellular senescence is a key feature in aging, but work on the heat shock response in cultured senescent (SEN) cells has largely been limited to fibroblasts. Given the prevalence of oxidative injury in the aging cardiovascular system, we investigated whether SEN primary human coronary artery endothelial cells have a diminished heat shock response and impaired proteostasis. In addition, we tested whether this downregulation of heat shock response can be mitigated by 17β-estradiol (E2), which has a critical cardioprotective role in women, as we have previously reported that E2 improves the heat shock response in endothelial cells (Hamilton KL, Mbai FN, Gupta S, Knowlton AA. Arterioscler Thromb Vasc Biol 24: 1628–1633, 2004). We found that SEN endothelial cells, despite their unexpectedly increased proteasome activity, had a diminished heat shock response and had more protein aggregation than early passage cells. SEN cells had increased oxidative stress, which promoted protein aggregation. E2 treatment did not decrease protein aggregation or improve the heat shock response in either early passage or SEN cells. In summary, cellular senescence in adult human endothelial cells is accompanied by increased oxidative stress and a blunting of proteostasis, and E2 did not mitigate these changes. NEW & NOTEWORTHY Senescent human endothelial cells have a diminished heat shock response and increased protein aggregates. Senescent human endothelial cells have increased basal oxidative stress, which increases protein aggregates. Physiological level of 17β-estradiol did not improve proteostasis in endothelial cells. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/proteostasis-in-senescent-endothelial-cells/ .

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Induction of heat shock response leads to apoptosis in endothelial cells previously exposed to endotoxin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.265.1.h165 ◽

1993 ◽

Vol 265 (1) ◽

pp. H165-H170 ◽

Cited By ~ 4

Author(s):

T. G. Buchman ◽

P. A. Abello ◽

E. H. Smith ◽

G. B. Bulkley

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Heat Shock ◽

Acute Phase ◽

Heat Shock Response ◽

Acute Phase Response ◽

Phase Response ◽

Heat Shock Gene ◽

Heat Shock Genes ◽

Shock Response

The homeostatic response of complex eukaryotes to the challenge of environmental stress includes the induction of several programs of gene expression; among them are those for the acute phase genes and those for the heat shock genes. In some systems, the heat shock response, which is often elicited by more severe stimuli, preempts the acute phase response, which is seen in response to less severe challenges, as well as constitutive gene expression. Nevertheless, each response appears to provide a natural selective advantage for survival of the organism in a toxic environment. However, when cultured porcine endothelial cells were exposed first to a nonlethal level of bacterial endotoxin lipopolysaccharide (LPS), an inducer of the acute phase response, and then, simultaneously to standard stimuli, which normally elicit a salutary heat shock response, the cells died manifesting a pattern of DNA fragmentation (nucleolysis) characteristic of programmed cell death (apoptosis). The treatment of LPS-exposed cells with cycloheximide to block protein synthesis reproduced the lethal apoptosis that had been elicited by the induction of heat shock gene expression. Therefore, the preemption of other programs of stress gene expression by the prioritized expression of heat shock genes is associated with apoptosis.

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205; PROTECTIVE EFFECT OF HEAT SHOCK RESPONSE AGAINST BOVINE PULMONARY ENDOTHELIAL CELLS INJURY INDUCED BY H2O2, and ITS MECHANISM

Shock ◽

10.1097/00024382-199401001-00206 ◽

1994 ◽

Vol 1 (Supplement) ◽

pp. 57

Author(s):

Ling Zong ◽

Jia-Lu You

Keyword(s):

Endothelial Cells ◽

Heat Shock ◽

Protective Effect ◽

Heat Shock Response ◽

Pulmonary Endothelial Cells ◽

Shock Response

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Human esophageal microvascular endothelial cells respond to acidic pH stress by PI3K/AKT and p38 MAPK-regulated induction of Hsp70 and Hsp27

AJP Cell Physiology ◽

10.1152/ajpcell.00474.2005 ◽

2006 ◽

Vol 291 (5) ◽

pp. C931-C945 ◽

Cited By ~ 47

Author(s):

Parvaneh Rafiee ◽

Monica E. Theriot ◽

Victoria M. Nelson ◽

Jan Heidemann ◽

Yasmin Kanaa ◽

...

Keyword(s):

Endothelial Cells ◽

Heat Shock ◽

P38 Mapk ◽

Heat Shock Response ◽

Acid Exposure ◽

Microvascular Endothelial Cells ◽

Acidic Ph ◽

Hsp70 Mrna ◽

Shock Response ◽

Microvascular Endothelial

The heat shock response maintains cellular homeostasis following sublethal injury. Heat shock proteins (Hsps) are induced by thermal, oxyradical, and inflammatory stress, and they chaperone denatured intracellular proteins. Hsps also chaperone signal transduction proteins, modulating signaling cascades during repeated stress. Gastroesophageal reflux disease (GERD) affects 7% of the US population, and it is linked to prolonged esophageal acid exposure. GERD is characterized by enhanced and selective leukocyte recruitment from esophageal microvasculature, implying activation of microvascular endothelium. We investigated whether phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK regulate Hsp induction in primary cultures of human esophageal microvascular endothelial cells (HEMEC) in response to acid exposure (pH 4.5). Inhibitors of signaling pathways were used to define the contribution of PI3K/Akt and MAPKs in the heat shock response and following acid exposure. Acid significantly enhanced phosphorylation of Akt and MAPKs in HEMEC as well as inducing Hsp27 and Hsp70. The PI3K inhibitor LY-294002, and Akt small interfering RNA inhibited Akt activation and Hsp70 expression in HEMEC. The p38 MAPK inhibitor (SB-203580) and p38 MAPK siRNA blocked Hsp27 and Hsp70 mRNA induction, suggesting a role for MAPKs in the HEMEC heat shock response. Thus acidic pH exposure protects HEMEC through induction of Hsps and activation of MAPK and PI3 kinase pathway. Acidic exposure increased HEMEC expression of VCAM-1 protein, but not ICAM-1, which may contribute to selective leukocyte (i.e., eosinophil) recruitment in esophagitis. Activation of esophageal endothelial cells exposed to acidic refluxate may contribute to GERD in the setting of a disturbed mucosal squamous epithelial barrier (i.e., erosive esophagitis, peptic ulceration).

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