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Niinuma, S.A.;  Lubbad, L.;  Lubbad, W.;  Moin, A.S.M.;  Butler, A.E. Therapeutic Interventions of Heat Shock Proteins. Encyclopedia. Available online: https://encyclopedia.pub/entry/40902 (accessed on 05 September 2024).
Niinuma SA,  Lubbad L,  Lubbad W,  Moin ASM,  Butler AE. Therapeutic Interventions of Heat Shock Proteins. Encyclopedia. Available at: https://encyclopedia.pub/entry/40902. Accessed September 05, 2024.
Niinuma, Sara Anjum, Laila Lubbad, Walaa Lubbad, Abu Saleh Md Moin, Alexandra E. Butler. "Therapeutic Interventions of Heat Shock Proteins" Encyclopedia, https://encyclopedia.pub/entry/40902 (accessed September 05, 2024).
Niinuma, S.A.,  Lubbad, L.,  Lubbad, W.,  Moin, A.S.M., & Butler, A.E. (2023, February 06). Therapeutic Interventions of Heat Shock Proteins. In Encyclopedia. https://encyclopedia.pub/entry/40902
Niinuma, Sara Anjum, et al. "Therapeutic Interventions of Heat Shock Proteins." Encyclopedia. Web. 06 February, 2023.
Therapeutic Interventions of Heat Shock Proteins
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24031838

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and post-menopausal women. PCOS is a multifactorial heterogeneous disorder associated with a variety of etiologies, outcomes, and clinical manifestations. Heat shock proteins (HSPs) play a significant role in the progression of this multifactorial disorder. Abnormal levels of HSPs are a common finding in women with PCOS, and it has been established that they are involved in many aspects of the condition, making them suitable targets for possible treatments. HSPs cannot broadly be labeled as “good” or “bad”, but simply integral factors in the mechanism of PCOS that, once disrupted, contribute to its pathogenesis and can potentially be modulated to alleviate the condition.

polycystic ovary syndrome heat shock proteins therapeutics insulin

1. Induction of Heat Shock Proteins through Exercise

Following diagnosis, exercise and lifestyle are first-line therapies advised for women with PCOS. This approach is mainly associated with increased HSPs in the body in response to stressors such as exercise. PCOS is an inflammatory disorder, and HSPs are known to be induced following stressors such as inflammation and oxidative stress [1]. HSP70 and HSP72 can block heat-induced apoptosis, which occurs through SAPK/JNK stimulation [2]. These proteins inhibit steps that occur upstream and play a role in minimizing the cleavage of poly (ADP-ribose) polymerase, a common death substrate protein [2]. Exercise induces the expression of HSPs, which would increase the inhibition of apoptosis and molecular damage as a result of disturbances in cell homeostasis in inflammatory states [3].
In one study, an 8-week moderate-intensity exercise program was performed to explore the effects of exercise on inducing the expression of HSPs and determine if this process is efficient in women with PCOS versus controls [4]. By the completion of the experiment, both groups showed some improvement in VO2 max, waist–hip ratio, BMI, and systolic blood pressure; however, these results were seen to a much lesser extent in the PCOS cohort. As for HSP72 expression in monocytes and lymphocytes, the control group showed a significant increase, while the increased trend in the PCOS cohort was not significant [4]. Thus, it was concluded that the HSP response to exercise was impaired in women with PCOS compared to the control group, and it was suggested that high-intensity exercise could have more favorable effects in inducing HSP activity [4]. It is, however, important to note that the small sample size, inability to evaluate the influence of obesity, and failure to measure serum HSP levels could have affected the outcomes of this study.
Further research into alternative methods to effectively induce HSPs, such as high-intensity interval training and resistance training, could have therapeutic implications for women with PCOS. Weightlifting has also been shown to be suitable for women with PCOS because it decreases testosterone levels, lowers IR, and, most importantly, increases metabolic rate [5]. More extensive studies are needed on this treatment approach as the exact association of these approaches with HSPs has not been adequately investigated.

2. Heat Shock Therapy

The role of heat shock therapy could be promising for patients with PCOS. A study has shown that heat therapy decreases sympathetic activity and enhances cardiovascular health in obese women with PCOS [6]. Heat therapy comprises several approaches, such as using a sauna, hot tub, and combined exercise heat stress [7]. This could be a promising approach since it has been clinically proven to improve cardiometabolic health in obese people [6]. Since obesity and PCOS both have potential cardiovascular risks, exploring and comparing heat shock therapy in both pathological conditions would be of interest.
It is important to note that there are not many pharmaceutical or lifestyle interventions that would decrease the cardiovascular risk for women with PCOS [6]. Most research and treatment options aimed at decreasing cardiovascular risk target men, thus it is crucial to further explore options and therapeutic interventions that can help women who have cardiovascular risk factors, including women with PCOS.
One study has found that, through a program of 30 one-hour heat therapy sessions conducted on obese women with PCOS, there were improvements in carotid and femoral artery wall thickness and decreased total cholesterol and fasting glucose [6]. Heat therapy clinically improved indicators of PCOS, such as lowering serum testosterone and normalizing menstrual cycles [8]. This emphasizes the role of heat therapy in metabolic and ovarian function in women with PCOS [8]. Another study showed that heat therapy in obese women with PCOS improved PCOS symptoms, systemic insulin sensitivity, whole-body glucose uptake, and insulin signaling in subcutaneous adipose tissue [8]. A single heat treatment lasting 20 min increased HSP72 levels maximally in all depots of white adipose tissue and also improved insulin signaling [9]. The beneficial improvements due to heat therapy can be attributed to increased levels of HSPs which act to inhibit inflammatory factors such as JNK [9]. Low levels of HSPs were found in adipose tissue of T2D patients, further supporting the association between increased levels of HSPs and metabolic health [10].
Nonetheless, these studies have limitations as they only included obese women with PCOS. Future research regarding heat therapy in non-obese women with PCOS remains to be explored. Further studies are also needed to analyze the effects of chronic heat treatment on the activity of HSPs.

3. Induction of HSPs to Treat Insulin Resistance

Although limited research has been conducted on the direct use of HSPs as therapy for PCOS, HSPs have been proven to combat insulin resistance. Patients with T2D were shown to have reduced gene expression of HSP72 [11]. According to a model proposed by Hooper and Hooper (2009), this decrease in HSPs is due to insulin resistance stimulated by inflammation in obesity [4]. When fatty acid levels are elevated in muscle fibers, this stimulates the formation of diacylglycerol and the activation of protein kinase C [12]. This leads to the phosphorylation of a critical residue on insulin receptor substrate-1 by IKK-beta and JNK, preventing the substrate from effectively interacting with the active insulin receptor [12]. HSP27 and HSP72 can prevent the activation of IKK-beta and JNK, thus allowing IRS-1 to appropriately bind to the receptor.
The use of bimoclomol and lipoic acid, inducers/co-inducers of HSPs, in obese rodents with insulin resistance was proven to improve insulin sensitivity [12]. BPG-15, another co-inducer of HSPs, was tested on insulin-resistant patients versus placebo and resulted in a notable increase in insulin sensitivity and glucose utilization [13]. This hypothesis was also tested on human subjects using heat shock therapy, transgenic overexpression in rodent models, and pharmacological drugs to induce HSP72 locally in skeletal muscle (as JNK phosphorylation was thought to be increased in skeletal muscle) [11]. Data showed that the increased expression of HSP72 prevented the phosphorylation of JNK and thus decreased diet/obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance [11].
Another study further tested the effects of HSPs using mild electrical stimulation (MES) in combination with heat shock [14]. Different doses and durations were tested in vivo and in vitro. This combined treatment for 10 min, twice weekly, could lower insulin resistance, insulin levels, and fasting blood glucose. In mice, this treatment stimulated the insulin signaling pathway and thus improved fat metabolism [14]. HSP70 was also shown to protect against oxidative stress injury in diabetes and insulin resistance. This action is stimulated by the reduced release of nitric oxide, which leads to inflammation and simultaneously induces HSP70 in an attempt to reduce it [15]. Considering that insulin resistance is a major symptom of PCOS, treating this aspect alone would undeniably improve patient quality of life. However, additional research exploring the effects of HSP induction on women with insulin resistance and PCOS is needed to ensure that these findings have therapeutic relevance.

4. Repression of Heat Shock Proteins through miRNAs

Although HSPs are generally believed to have a protective role, there is evidence suggesting that HSPs play a role in exacerbating the progression of PCOS [16]. MicroRNAs play a significant role in various diseases, such as cancers, metabolic disorders, and PCOS. HSP function is regulated by differing miRNAs, and hence, they have been a common target for experimental cancer therapies [17]. Researchers have applied the same methodology to PCOS because of the known involvement of miRNAs in the condition. The presence of miRNAs in follicular fluid allows them to influence follicular development and regulate dysfunction in granulosa cells that could otherwise lead to abnormalities such as PCOS [16]. An experiment conducted on DHT-induced rats revealed that 24% of potential miRNAs were differentially expressed in the PCOS group versus controls [16][18]. Another study used an RNase III enzyme necessary for the biogenesis of miRNAs, Dicer 1, to showcase their effects on ovarian function [19]. Knockout of Dicer 1 in mice led to infertility, decreased ovarian weight, decreased ovulation, disrupted the formation of the corpus luteum, and increased synthesis of cysts on the oviducts [19].
Due to the prevalence of miRNAs in ovarian function and their ability to influence heat shock activity, a study investigated the use of miR-144-3p to reduce HSP activity and whether that would yield favorable results in women with PCOS [16]. Initially, decreased expression of miR-144-3p and increased HSP70 expression were found in women with PCOS [16]. The miRNA was then upregulated/downregulated to measure its effects on HSPs. Upregulation of miR-144-3p led to stimulation of granulosa cell survival/proliferation and repressed cell apoptosis. Furthermore, an inhibitory effect on serum testosterone, estrogen, and LH levels was observed, and FSH was increased. Downregulation of the protein had opposite effects and contributed to the progression of endocrine disorders and ovarian weight. HSP70 was also confirmed as a direct target, as its expression was reduced by miR-144-3p mimics and induced by inhibitors. Decreased HSP70 levels improved granulosa cell proliferation, reduced apoptosis, decreased abnormal ovarian weight, and benefited endocrine disorders.
Anti-miR-144-3p applied in vivo increased serum testosterone, estradiol, and LH, but knockdown of HSP70 was able to minimize this increase [16]. Hence, targeting miRNAs could be a promising avenue for treating PCOS, but further research is necessary to increase knowledge about this therapeutic approach.
Besides miR-144-3p, using other microRNAs to modulate HSP activity might yield useful results as a treatment option for PCOS. Table 1 summarizes the roles of different microRNAs in regulating the activity of HSPs. However, it should be noted that limited research is available on the effect of microRNAs on the activity of HSPs in the context of PCOS.
Table 1. A list of possible microRNAs and their role in the regulation of HSPs. These microRNAs may act as potential treatment options for modulating the activity of HSPs to yield favorable results in women with PCOS.
MicroRNA Role in Regulation of HSPs
miR-570 [20] miR-570 was found to affect tumor cell growth and migration by targeting the HSP chaperone network
miR-223 [21] miR-223 can inhibit cell proliferation and increase cell apoptosis by targeting HSP 70
miR-550a-3p [22] miR-550a-3p can have antiproliferative and proapoptotic effects in prostate and ovarian cancer cells by inhibiting HSP90AA1
miR-1 [23] miR-1 was found to play a role in nitric oxide-induced apoptosis in osteoblasts by targeting HSP70
Despite these promising findings, there are some obstacles to using HSPs therapeutically. It is challenging to ensure that the specific HSP is upregulated in the intended tissue, at the correct level/specificity, and at a suitable time together with all the necessary co-chaperones present to yield the desired results [24]. It is likely that pharmaceutical inducers may not be able to reach the desired cells or bring about the intended effects. Moreover, research combining heat therapy and exercise has still not been explored, which could potentially be promising for considering the additive benefits of both therapeutic interventions.

References

  1. Sharma, H.S.; Westman, J.A.N. 17—The Heat Shock Proteins and Hemeoxygenase Response in Central Nervous System Injuries. In Blood-Spinal Cord and Brain Barriers in Health and Disease; Sharma, H.S., Westman, J., Eds.; Academic Press: San Diego, CA, USA, 2004; pp. 329–360.
  2. Mosser, D.D.; Caron, A.W.; Bourget, L.; Denis-Larose, C.; Massie, B. Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol. Cell Biol. 1997, 17, 5317–5327.
  3. Ikwegbue, P.C.; Masamba, P.; Oyinloye, B.E.; Kappo, A.P. Roles of Heat Shock Proteins in Apoptosis, Oxidative Stress, Human Inflammatory Diseases, and Cancer. Pharmaceuticals 2017, 11, 2.
  4. Vince, R.V.; Kirk, R.J.; Aye, M.M.; Atkin, S.L.; Madden, L.A. Impaired heat shock protein 72 expression in women with polycystic ovary syndrome following a supervised exercise programme. Cell Stress Chaperones 2020, 25, 73–80.
  5. Pericleous, P.; Stephanides, S. Can resistance training improve the symptoms of polycystic ovary syndrome? BMJ Open Sport Exerc. Med. 2018, 4, e000372.
  6. Ely, B.R.; Francisco, M.A.; Halliwill, J.R.; Bryan, S.D.; Comrada, L.N.; Larson, E.A.; Brunt, V.E.; Minson, C.T. Heat therapy reduces sympathetic activity and improves cardiovascular risk profile in women who are obese with polycystic ovary syndrome. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2019, 317, R630–R640.
  7. Ely, B.R.; Clayton, Z.S.; McCurdy, C.E.; Pfeiffer, J.; Minson, C.T. Meta-inflammation and cardiometabolic disease in obesity: Can heat therapy help? Temperature (Austin) 2018, 5, 9–21.
  8. Ely, B.R.; Clayton, Z.S.; McCurdy, C.E.; Pfeiffer, J.; Needham, K.W.; Comrada, L.N.; Minson, C.T. Heat therapy improves glucose tolerance and adipose tissue insulin signaling in polycystic ovary syndrome. Am. J. Physiol. Endocrinol. Metab. 2019, 317, E172–E182.
  9. Rogers, R.S.; Beaudoin, M.S.; Wheatley, J.L.; Wright, D.C.; Geiger, P.C. Heat shock proteins: In vivo heat treatments reveal adipose tissue depot-specific effects. J. Appl. Physiol. (1985) 2015, 118, 98–106.
  10. Hooper, P.L.; Hooper, P.L. Inflammation, heat shock proteins, and type 2 diabetes. Cell Stress Chaperones 2009, 14, 113–115.
  11. Chung, J.; Nguyen, A.K.; Henstridge, D.C.; Holmes, A.G.; Chan, M.H.; Mesa, J.L.; Lancaster, G.I.; Southgate, R.J.; Bruce, C.R.; Duffy, S.J.; et al. HSP72 protects against obesity-induced insulin resistance. Proc. Natl. Acad. Sci. USA 2008, 105, 1739–1744.
  12. McCarty, M.F. Induction of heat shock proteins may combat insulin resistance. Med. Hypotheses 2006, 66, 527–534.
  13. Literáti-Nagy, B.; Kulcsár, E.; Literáti-Nagy, Z.; Buday, B.; Péterfai, E.; Horváth, T.; Tory, K.; Kolonics, A.; Fleming, A.; Mandl, J.; et al. Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: A proof of concept randomized double-blind clinical trial. Horm. Metab. Res. 2009, 41, 374–380.
  14. Morino, S.; Kondo, T.; Sasaki, K.; Adachi, H.; Suico, M.A.; Sekimoto, E.; Matsuda, T.; Shuto, T.; Araki, E.; Kai, H. Mild electrical stimulation with heat shock ameliorates insulin resistance via enhanced insulin signaling. PLoS ONE 2008, 3, e4068.
  15. Molina, M.N.; Ferder, L.; Manucha, W. Emerging Role of Nitric Oxide and Heat Shock Proteins in Insulin Resistance. Curr. Hypertens. Rep. 2016, 18, 1.
  16. Sørensen, A.E.; Wissing, M.L.; Salö, S.; Englund, A.L.; Dalgaard, L.T. MicroRNAs Related to Polycystic Ovary Syndrome (PCOS). Genes 2014, 5, 684–708.
  17. Ozgur, A.; Tutar, L.; Tutar, Y. Regulation of Heat Shock Proteins by miRNAs in human breast cancer. Microrna 2014, 3, 118–135.
  18. Qu, B.; Zhao, Q.; Ma, Q.; Yang, T.; Li, X.; Chen, Y.; Yang, J.; Zhang, Y. Overexpression of miR-144-3p alleviates polycystic ovaries syndrome through targeting expression of HSP-70. Gene Ther. 2022, 29, 217–226.
  19. Rosenfield, R.L.; Ehrmann, D.A. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr. Rev. 2016, 37, 467–520.
  20. Okusha, Y.; Guerrero-Gimenez, M.E.; Lang, B.J.; Borges, T.J.; Stevenson, M.A.; Truman, A.W.; Calderwood, S.K. MicroRNA-570 targets the HSP chaperone network, increases proteotoxic stress and inhibits mammary tumor cell migration. Sci. Rep. 2022, 12, 15582.
  21. Ou-Yang, Y.; Liu, Z.L.; Xu, C.L.; Wu, J.L.; Peng, J.; Peng, Q.H. miR-223 induces retinal ganglion cells apoptosis and inflammation via decreasing HSP-70 in vitro and in vivo. J. Chem. Neuroanat. 2020, 104, 101747.
  22. El Bezawy, R.; Percio, S.; Ciniselli, C.M.; De Cesare, M.; Colella, G.; Dugo, M.; Veneroni, S.; Doldi, V.; Martini, S.; Baratti, D.; et al. miR-550a-3p is a prognostic biomarker and exerts tumor-suppressive functions by targeting HSP90AA1 in diffuse malignant peritoneal mesothelioma. Cancer Gene Ther. 2022, 29, 1394–1404.
  23. Lee, Y.E.; Hong, C.Y.; Lin, Y.L.; Chen, R.M. MicroRNA-1 participates in nitric oxide-induced apoptotic insults to MC3T3-E1 cells by targeting heat-shock protein-70. Int. J. Biol. Sci. 2015, 11, 246–255.
  24. Kalmar, B.; Greensmith, L. Induction of heat shock proteins for protection against oxidative stress. Adv. Drug Deliv. Rev. 2009, 61, 310–318.
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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Sara Anjum Niinuma
,
Laila Lubbad
,
Walaa Lubbad
,
Abu Saleh Md Moin
,
Alexandra E. Butler
View Times: 336
Revisions: 2 times (View History)
Update Date: 08 Feb 2023
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