Hsp70 in myocardial ischaemia

Huang

J of Cellular Biochemistry

et al. 2002

150

172

The rapid synthesis of heat shock proteins (Hsps) in cells subjected to environmental challenge is controlled by heat shock transcription factor-1 (Hsf1). Regulation of Hsps by Hsf1 is highly complex and, in the whole organism, remains largely unexplored. In this study, we have used mouse embryo fibroblasts and bone marrow progenitor cells from hsf1-/- mice as well as hsp70.3-lacZ knock-in mice bred on the hsf1deficient genetic background (hsf1-/--hsp70.3+/--lacZ), to further elucidate the function of Hsf1 and its participation as a transcriptional activator of Hsp70 synthesis under normal or heat-induced stress conditions in vitro and in vivo. The results revealed that heat-induced Hsp70 expression in mouse tissue is entirely controlled by Hsf1, whereas its activity is not required for tissue-specific constitutive Hsp70 expression. We further demonstrate that Hsf1 is critical for maintaining cellular integrity after heat stress and that cells from hsf1-/- mice lack the ability to develop thermotolerance. This deficiency is explained by the elimination of stress-inducible Hsp70 and Hsp25 response in the absence of Hsf1 activity, leading to a lack of Hsp-mediated inhibition of apoptotic cell death via both caspase-dependent and caspase-independent pathways. The pivotal role of the Hsf1 transactivator in regulating rapid synthesis of Hsps as a critical cellular defense mechanism against environmental stress-induced damage is underlined.

Section: Inducible Hsps Exhibit Basal Expression In Different Tissuesmentioning

confidence: 97%

Targeted disruption of hsf1 leads to lack of thermotolerance and defines tissue‐specific regulation for stress‐inducible Hsp molecular chaperones

Huang

J of Cellular Biochemistry

et al. 2002

150

172

“…Higher levels of HSP70 in the myocardial tissue have been correlated with smaller infarct size and improved tolerance to ischaemic injury in experimental animals [29] as well as in humans [30]. …”

Section: Discussionmentioning

confidence: 99%

Association of Met439Thr Substitution in Heat Shock Protein 70 Gene with Postoperative Atrial Fibrillation and Serum HSP70 Protein Levels

et al. 2007

Background: Atrial fibrillation (AF) is a common arrhythmia encountered following cardiac surgery. Previously, we have shown that higher expression of heat shock protein (HSP) 70 was associated with decreased incidence of postoperative AF (PoAF), suggestive of an antiarrhythmic role. Objective: We have hypothesised that Met493Thr substitution of one of the important hsp70 genes may cause loss of these protective antiarrhythmic effects. We therefore set out to examine the influence of hsp70 genotype on the incidence of PoAF. Methods and Results: We prospectively recruited 244 Caucasian patients undergoing elective coronary artery bypass surgery. The median age was 65 years (40–80 years). PoAF was defined as the characteristic arrhythmia lasting for at least 15 min, occurring within first week following surgery and requiring treatment. This occurred in 48 patients (19.7%). Validated Met493Thr substitution in hsp70-Hom was determined using established techniques. Of 244 patients, genotype was determined for 242 cases. The three genotypes (MM, MT, and TT) were present at frequencies of 0.66, 0.31, and 0.03, respectively, and were in Hardy-Weinberg equilibrium. In unifactorial analysis patients carrier or homozygous for 493Thr mutation had significantly higher incidence of PoAF (Pearson χ² = 4.3, p = 0.037). Multivariate analysis confirmed the positive association of hsp70-Hom with PoAF (OR, 2.43; p = 0.016) independent of age, sex, previous myocardial infarction, number of distal anastomoses, and duration of ventilation, respectively. Serum HSP70 was ranging from 0.74 to 31.91 ng/ml (median, 2.89) and was not correlated with PoAF. Presence of 493Thr mutation was also significantly correlated with higher levels of serum HSP70 (p = 0.009). Conclusions: Our data show that a mutation in hsp70-Hom gene is associated with higher incidence of PoAF. These findings are consistent with our previous results and may suggest that patients harbouring this substitution will have less endogenous myocardial protection against AF in stressful situations.

“…Restoration of normal cardiac function would require removal of denatured cardiac protein and reestablishment of normal cardiac protein synthesis. The heat stress proteins, which are synthesized in all organisms in response to stresses such as heat and ischemia, may well play a pivotal role in providing protection from a subsequent stress (1,2). The heat stress response is known to be initiated by activation of the heat shock factor (HSF) 1 1, which is normally present in unstressed cells and rapidly trimerizes in response to metabolic stress.…”

Section: Introductionmentioning

confidence: 99%

Specific induction of the 70-kD heat stress proteins by the tyrosine kinase inhibitor herbimycin-A protects rat neonatal cardiomyocytes. A new pharmacological route to stress protein expression?

Morris

Cumming²,

Latchman³

et al. 1996

J. Clin. Invest.

Heat shock protein (hsp) induction by stressful stimuli such as heat and ischemia is known to protect cardiac cells from severe stress. The ability to induce hsp's in the heart directly by "nonstressful" means would potentially have important clinical implications. In noncardiac cells, the tyrosine kinase inhibitor herbimycin-A has been shown to induce the 72-kD hsp. We therefore examined whether herbimycin-A and another tyrosine kinase inhibitor, genistein, could induce 70-kD hsp's in primary cultures of rat neonatal cardiomyocytes, and whether these treatments protect against severe stress. Primary cardiomyocytes were incubated with herbimycin-A or genistein. hsp induction was measured 16-20 h later by Western blotting. Cell survival after subsequent lethal heat stress or simulated ischemia was assessed using trypan blue exclusion and released lactate dehydrogenase activity.