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The role of heat shock protein 70 in the protective effect of YC-1 on ?-amyloid-induced toxicity in differentiated PC12 cells.

ABSTRACT: Neurodegenerative brain disorders such as Alzheimer's disease (AD) have been well investigated. However, significant methods for the treatment of the progression of AD are unavailable currently. Heat shock protein 70 (Hsp70) plays important roles in neural protection from stress by assisting cellular protein folding. In this study, we investigated the effect and the molecular mechanism of YC-1, an activator of guanylyl cyclase (GC), on A?25-35-induced cytotoxicity in differentiated PC12 cells. The results of this study showed that A?25-35 (10 µM) significantly increased p25 protein production in a pattern that was consistent with the increase in ?-calpain expression. Moreover, A?25-35 significantly increased tau hyperphosphorylation and induced differentiated PC12 cell death. YC-1 (0.5-10 µM) prevented the cell death induced by A?25-35. In addition, YC-1 (1, 10 µM) significantly blocked A?25-35-induced ?-calpain expression and decreased the formation of p25 and tau hyperphosphorylation. Moreover, YC-1 (5-20 µM) alone or combined with A?25-35 (10 µM) significantly increased the expression of Hsp70 in differentiated PC12 cells. The neuroprotective effect of YC-1 was significantly attenuated by an Hsp70 inhibitor (quercetin, 50 µM) or in PC12 cells transfected with an Hsp70 small interfering RNA. However, pretreatment of cells with the GC inhibitor ODQ (10 µM) did not affect the neuroprotective effect of YC-1 against A?25-35 in differentiated PC12 cells. These results suggest that the neuroprotective effect of YC-1 against A?25-35-induced toxicity is mainly mediated by the induction of Hsp70. Thus, YC-1 is a potential agent against AD.

SUBMITTER: Tsai YC

PROVIDER: S-EPMC3724837 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The role of heat shock protein 70 in the protective effect of YC-1 on β-amyloid-induced toxicity in differentiated PC12 cells.

Tsai Yung-Chieh YC Lee Yen-Mei YM Lam Kwok-Keung KK Lin Jui-Fen JF Wang Jhi-Joung JJ Yen Mao-Hsiung MH Cheng Pao-Yun PY

PloS one 20130726 7

Neurodegenerative brain disorders such as Alzheimer's disease (AD) have been well investigated. However, significant methods for the treatment of the progression of AD are unavailable currently. Heat shock protein 70 (Hsp70) plays important roles in neural protection from stress by assisting cellular protein folding. In this study, we investigated the effect and the molecular mechanism of YC-1, an activator of guanylyl cyclase (GC), on Aβ25-35-induced cytotoxicity in differentiated PC12 cells. T ...[more]

PMID: 23922702

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Project description:BackgroundTransgenic mice have been used to examine the role of heat shock protein (HSP)72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70beta gene ([+] HSP72) and transgene-negative littermate controls ([-] HSP72), under pentobarbital sodium anesthesia, were subjected to heat stress to induce heatstroke. It was found that the overexpression of HSP72 in multiple organs improved survival during heatstroke by reducing hypotension and cerebral ischemia and damage in mice. Herein we attempted to further assess the effect of heat exposure on thermoregulatory function, hypothalamic integration, and survival in unrestrained, unanesthetized [+]HSP72 and compare with those of [-]HSP72. In this research with the transgenic mice, we first conducted several biochemical, physiologic and histological determinations and then investigated the beneficial effects of HSP72 overexpression on the identified hypothalamic deficits, thermoregulatory dysfunction, and mortality during heatstroke.ResultsWe report here that when [-]HSP72 mice underwent heat stress (ambient temperature 42.4 degrees C for 1 h), the fraction survival and core temperature at 4 h after heat stress were found to be 0 of 12 and 34.2 degrees C +/- 0.4 degrees C, respectively. Mice that survived to day 4 after heat stress were considered as survivors. In [+]HSP72 mice, when exposed to the same heat treatment, both fraction survival and core temperature values were significantly increased to new values of 12/12 and 37.4 degrees C +/- 0.3 degrees C, respectively. Compared to [-]HSP mice, [+]HSP72 mice displayed lower hypothalamic values of cellular ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and damage (e.g., glycerol) markers, pro-oxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), pro-inflammatory cytokines (e.g., interleukin-1beta and tumor necrosis factor-alpha), and neuronal damage score evaluated 4 h after heat stress. In contrast, [+]HSP72 mice had higher hypothalamic values of antioxidant defences (e.g., glutathione peroxidase and glutathione reductase), ATP, and HSP72 expression.ConclusionThis study indicates that HSP72 overexpression appears to be critical to the development of thermotolerance and protection from heat-induced hypothalamic ischemic and oxidative damage.

Project description:The purpose of this study was to investigate the alterations in serum heat shock protein (Hsp) 70 levels during a 15-consecutive-day intermittent heat-exercise protocol in a 29-year-old male ultra marathon runner. Heat acclimation, for the purpose of physical activities in elevated ambient temperatures, has numerous physiological benefits including mechanisms such as improved cardiac output, increased plasma volume and a decreased core temperature (T (c)). In addition to the central adaptations, the role of Hsp during heat acclimation has received an increasing amount of attention. The acclimation protocol applied was designed to correspond with the athlete's tapering period for the 2007 Marathon Des Sables. The subject (VO(2)max = 50.7 ml.kg(-1).min(-1), peak power output [PPO] = 376 W) cycled daily for 90 min at a workload corresponding to 50% of VO(2)max in a temperature-controlled room (average WBGT = 31.9 +/- 0.9 degrees C). Venous blood was sampled before and after each session for measurement of serum osmolality and serum Hsp70. In addition, T (c), heart rate (HR) and power output (PO) was measured throughout the 90 min to ensure that heat acclimation was achieved during the 15-day period. The results show that the subject was successfully heat acclimated as seen by the lowered HR at rest and during exercise, decreased resting and exercising T (c) and an increased PO. The heat exercise resulted in an initial increase in Hsp70 concentrations, known as thermotolerance, and the increase in Hsp70 after exercise was inversely correlated to the resting values of Hsp70 (Spearman's rank correlation = -0.81, p < 0.01). Furthermore, the 15-day heat-exercise protocol also increased the basal levels of Hsp70, a response different from that of thermotolerance. This is, as far as we are aware, the first report showing Hsp70 levels during consecutive days of intermittent heat exposure giving rise to heat acclimation. In conclusion, a relatively longer heat acclimation protocol is suggested to obtain maximum benefit of heat acclimation inclusive of both cellular and systemic adaptations.

Dataset Information

The role of heat shock protein 70 in the protective effect of YC-1 on ?-amyloid-induced toxicity in differentiated PC12 cells.

Publications

The role of heat shock protein 70 in the protective effect of YC-1 on β-amyloid-induced toxicity in differentiated PC12 cells.

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