Serum Heat Shock Protein 70 Concentration in Relation to Polycystic Ovary Syndrome in a Non-Obese Chinese Population

Background Polycystic ovary syndrome (PCOS) represents the most common cause of anovulatory infertility and affects 6-15% of women of reproductive age. However, the underlying etiology is still poorly understood. In this study, we attempted to examine the association between circulating heat shock protein 70 (Hsp70) concentrations and PCOS in a non-obese Chinese population. Methods and Results Human peripheral blood from 52 patients with PCOS and 57 healthy controls, matched for age and BMI, were analyzed. Women with PCOS were found to have significantly higher fasting insulin (FI) levels, as well as Insulin resistance index (HOMA-IR) (P < 0.05). Identically, markers of oxidative stress (malondialdehyde (MDA), 8-Hydroxy-desoxyguanosine (8-OHdG), Nitric oxide (NO)) and inflammation (tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP)) were markedly increased when compared to controls (P < 0.05). Elevated serum Hsp70 was positively correlated with IR, oxidative stress and inflammation in PCOS, even after adjustment for age, BMI and gynecologic inflammation (GI). The receiver-operating characteristic curve (ROC) analysis yielded notably different discriminative value for PCOS, with or without an addition of Hsp70 (areas under the curves were 0.884 (95% CI 0.822-0.946) vs. 0.822 (95% CI 0.744-0.900); P for difference = 0.015). Conclusions and Significance Increased serum Hsp70 levels are associated with the combination of IR, oxidative stress and low-grade chronic inflammation in PCOS individuals, which provides supportive evidence that Hsp70 plays a key role in the pathogenesis of PCOS. More consequent studies were warranted to confirm the clinical utility of circulating Hsp70, especially in diagnosis and prognosis of PCOS and its long-term health cost.

[1]  U. Brunk,et al.  Protective induction of Hsp70 in heat‐stressed primary myoblasts: Involvement of MAPKs , 2013, Journal of cellular biochemistry.

[2]  B. Park,et al.  Cardioprotective molecules are enriched in beating cardiomyocytes derived from human embryonic stem cells. , 2013, International journal of cardiology.

[3]  M. Murri,et al.  Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. , 2013, Human reproduction update.

[4]  T. Buchanan,et al.  High-fat diet is associated with obesity-mediated insulin resistance and β-cell dysfunction in Mexican Americans. , 2013, The Journal of nutrition.

[5]  W. Klepetko,et al.  Discrimination of clinical stages in non-small cell lung cancer patients by serum HSP27 and HSP70: a multi-institutional case-control study. , 2012, Clinica chimica acta; international journal of clinical chemistry.

[6]  A. Esteghamati,et al.  The dual behavior of heat shock protein 70 and asymmetric dimethylarginine in relation to serum CRP levels in type 2 diabetes. , 2012, Gene.

[7]  Dan Zhang,et al.  [The role of oxidative stress in the pathogenesis of polycystic ovary syndrome]. , 2012, Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition.

[8]  O. Dekkers,et al.  PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. , 2011, Human reproduction update.

[9]  H. Escobar-Morreale,et al.  Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. , 2011, Fertility and sterility.

[10]  L. Moran,et al.  Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. , 2010, Human reproduction update.

[11]  L. Moran,et al.  Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan , 2010, BMC medicine.

[12]  B. Nicklas,et al.  Effect of exercise training on chronic inflammation. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[13]  A. Esteghamati,et al.  Increased serum HSP70 levels are associated with the duration of diabetes , 2010, Cell Stress and Chaperones.

[14]  R. Norman,et al.  Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. , 2010, The Journal of clinical endocrinology and metabolism.

[15]  Z. Prohászka,et al.  Circulating heat shock protein 70 (HSPA1A) in normal and pathological pregnancies , 2010, Cell Stress and Chaperones.

[16]  L. Mcnaughton,et al.  In vitro heat shock of human monocytes results in a proportional increase of inducible Hsp70 expression according to the basal content , 2010, Amino Acids.

[17]  W. van Eden,et al.  A novel heat-shock protein coinducer boosts stress protein Hsp70 to activate T cell regulation of inflammation in autoimmune arthritis. , 2010, Arthritis and rheumatism.

[18]  F. Hu,et al.  Plasma levels of Hsp70 and anti-Hsp70 antibody predict risk of acute coronary syndrome , 2010, Cell Stress and Chaperones.

[19]  P. Lavie,et al.  Heat‐shock protein 70: expression in monocytes of patients with sleep apnoea and association with oxidative stress and tumour necrosis factor‐α , 2010, Journal of sleep research.

[20]  J. Kirwan,et al.  Evidence of proatherogenic inflammation in polycystic ovary syndrome. , 2009, Metabolism: clinical and experimental.

[21]  Linda Greensmith,et al.  Induction of heat shock proteins for protection against oxidative stress. , 2009, Advanced drug delivery reviews.

[22]  S. Shumak Even lean women with PCOS are insulin resistant , 2009, BMJ : British Medical Journal.

[23]  J. Florez,et al.  The role of HSP70 on ENPP1 expression and insulin-receptor activation , 2009, Journal of Molecular Medicine.

[24]  C. Yılmaz,et al.  Oxidative Stress Markers in Young Patients with Polycystic Ovary Syndrome, The Relationship between Insulin Resistances , 2008, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[25]  Jason Chung,et al.  HSP72 protects against obesity-induced insulin resistance , 2008, Proceedings of the National Academy of Sciences.

[26]  Irun R Cohen,et al.  Biomarkers, self-antigens and the immunological homunculus. , 2007, Journal of autoimmunity.

[27]  C. Duman,et al.  Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation. , 2004, The Journal of clinical endocrinology and metabolism.

[28]  T. Perls,et al.  Cardiovascular Disease Delay in Centenarian Offspring: Role of Heat Shock Proteins , 2004, Annals of the New York Academy of Sciences.

[29]  M. Senchyna,et al.  Expression of prostaglandin G/H synthase (PGHS) and heat shock protein-70 (HSP-70) in the corpus luteum (CL) of prostaglandin F2 alpha-treated immature superovulated rats. , 2004, Canadian journal of physiology and pharmacology.

[30]  A. Butte,et al.  Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Cleves From the Help Desk: Comparing Areas under Receiver Operating Characteristic Curves from Two or more Probit or Logit Models , 2002 .

[32]  A. Balen,et al.  Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference? , 2002, Clinical endocrinology.

[33]  K. Eriksson,et al.  Decreased expression of heat shock protein 72 in skeletal muscle of patients with type 2 diabetes correlates with insulin resistance. , 2002, Diabetes.

[34]  J. Connell,et al.  Low grade chronic inflammation in women with polycystic ovarian syndrome. , 2001, The Journal of clinical endocrinology and metabolism.

[35]  D. Wink,et al.  A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. , 2001, Nitric oxide : biology and chemistry.

[36]  Gerardo Heiss,et al.  Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study , 1999, The Lancet.

[37]  J. Corton,et al.  Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. , 1998, Immunological investigations.

[38]  D. Jakubowicz,et al.  Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. , 1997, The Journal of clinical endocrinology and metabolism.

[39]  D. Yellon,et al.  Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. , 1995, The Journal of clinical investigation.

[40]  M. Richard,et al.  Protective effects of hsp70 in inflammation , 1994, Experientia.

[41]  I. Malyshev The Role of HSP70 in the Protection of: (A) The Brain in Alzheimer’s Disease and (B) The Heart in Cardiac Surgery , 2013 .

[42]  Enrico Carmina,et al.  Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. , 2012, Fertility and sterility.

[43]  R. Seneviratne,et al.  Phenotype and metabolic profile of South Asian women with polycystic ovary syndrome (PCOS): results of a large database from a specialist Endocrine Clinic. , 2011, Human reproduction.

[44]  S. Zoungas,et al.  Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. , 2010, Fertility and sterility.

[45]  B. Yıldız,et al.  Insulin resistance in polycystic ovary syndrome: maker or marker? , 2010 .

[46]  S. Bhattacharya,et al.  Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. , 2009, Reproductive biomedicine online.

[47]  J. Kirwan,et al.  Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. , 2006, The Journal of clinical endocrinology and metabolism.

[48]  M. McCarty Induction of heat shock proteins may combat insulin resistance. , 2006, Medical hypotheses.

[49]  B. Fauser,et al.  Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). , 2004, Human reproduction.