| By Nadine Shaban |
It wasn’t too long ago that I was sitting in my advisors office and he was giving me a lecture about some sort of life event. His lectures about life still resonate with me after all this time. I remember one particular story about one of his friends. They were telling him how there was interest in getting a quote from him regarding a specific protein he researched; they wanted to put it on a supplement bottle. This got me thinking about how much research and development is growing in the supplement industry. And, as a result, so are the types of supplements landing on store shelves.
It seems like there is a new discovery about a certain amino acid, and/or protein daily. And, enterprising supplement company owners rush to utilize the hype; throwing a bottle of whatever together and make some money. This article is about a new supplement in town that actually works. Don’t crap your pants looking for it, it isn’t on store shelves. You can create this new supplement yourself. You have permission to crap your pants now. Unfortunately it’s not as easy as popping a pill, but let me tell you it’s as COST EFFICIENT and you will get much more health benefits then one pill you pop. Sit back, relax and enjoy my review on a protein called Heat Shock Protein (HspP70).
Warning: Nadine Shaban has just suffered a horrific lab accident; being bombarded with science gamma rays. She has turned into the Science She-Hulk, smashing your brain with some science.
Science is uncovering gender differences that go beyond the reproductive and endocrine system. Cardiovascular disease (CVD) is the major cause of death globally and will continue to escalate over the next decade. More importantly, CVD is the leading cause of death in women, with diabetes greatly increasing this risk. Scientific advances confirm the remarkable benefits of exercise, as it is well established that physical activity is an effective practice for reducing risks of many chronic diseases, such as Type 2 Diabetes (T2D) and CVD. For example, moderately intense physical activity (e.g., walking) reduces both CVD and T2D incidence rates, and decreases metabolic risk factors for developing CVD and T2D (5) (e.g., reduces blood pressure, improve lipid profiles in patients with T2D, and improves insulin sensitivity).
Premenopausal women have a cardio protective advantage over men, as estrogen can reduce the appearance and severity of CVD. It is important to note that this protective barrier is attenuated in postmenopausal women, as estrogen levels decreased. In contrast to this advantage, females are more likely to die when an incident transpires. Interestingly, due to the estrogenic protection in combination with greater molecular advantages, premenopausal women require a greater stressor in order to induce a cardiovascular event. Post trauma, females experience poorer outcomes, and are not able to return to their normal quality of life, compared to men as they have a better recovery process. Therefore, it may be more difficult for premenopausal women to develop CVD. However, when they do, their recovery is more severe than males. Nonetheless, premenopausal women encounter an unfortunate outcome in terms of physical activity as they do not attain the same protective benefits as males. During exercise, estrogen may inhibit vital adaptations, including the expression of the cardio protective 70-kDa heat-shock protein, Hsp70.
Before I dig into the good stuff “Hsp70”, let’s take a step to look at why females rock and why when we work out and weight train we rock even more… not that I am biased or anything!
Before I dig into the good stuff “Hsp70”, let’s take a step to look at why females rock and why when we work out and weight train we rock even more… not that I am biased or anything!
UNDERSTANDING HOW ESTROGEN WORKS
Hormones are vital to the cellular function of the human body. Estrogens are steroid hormones essential to the human endocrine system. They have many diverse physiological, pathophysiological, and psychological functions in different tissues and cell types of both males and females. Estrogen controls the development of essential reproductive organs, as well as aiding in maintaining homeostasis in specific organs. It plays a key role in bone development, the central nervous system and in the cardiovascular system. To add to its list of important functions; estrogen is a signaling molecule that stimulates critical enzymes, maintains cell function, and synthesizes many new proteins.
In the most basic manner, estrogen binds to its intracellular receptor located in the cytoplasm or nucleus. Estrogen receptors (ER) have both a DNA binding domain, that activates transcriptional activity through hormone response elements, and a ligand binding domain. Therefore, in the absence of estrogen, ER resides in the cytoplasm in an inactive form. Upon ligand/estrogen binding, the ER is activated. The ligand-ER complex migrates to the nucleus, where it is capable of binding with a specific DNA sequence on a target gene. Subsequently, it activates the hormone response element, and initiates gene transcription.
Recently, science is discovering estrogen’s ability to have non-genomic effects. G –protein coupled receptors, localized to the cellular membrane are activated by estrogen. Once activated, a cascade effect occurs to promote activation of the adenylyl cyclase/cAMP-dependent protein kinase A (PKA) pathway. This is important as PKA signaling mediates anti-apoptotic effects, ensuring cell survival. Once bound to estrogen, PKA can execute its various protective functions. As mentioned above, estrogen is a rapid acting signal molecule that can phosphorylate existing proteins; as well as induce protein synthesis through gene transcription and translation. Therefore, estrogen has both genomic and non-genomic effects.
PHYSICAL ACTIVITY REDUCES THE RISK OF CHRONIC DISEASES
Apart from the cardio protective and pathophysiological benefits of estrogen, physical inactivity is a significant predictor for developing T2D, CVD, and other metabolic/chronic disorders (5). A sedentary lifestyle should be considered an important modifiable risk factor that the general population can manipulate. As the exact exercise prescription is still a debate (intensity, frequency, and duration), researchers agree that physical activity provides benefits that outweigh any hormonal measurement. Moderately intense physical activity (e.g., walking) reduces both CVD and T2D incidence rate, and decreases metabolic risk factors for developing CVD and T2D (5)(e.g., reduce blood pressure, decrease fat mass while improving/maintaining lean muscle mass(60), improve lipid profiles in patients with T2D, and improve insulin sensitivity(21)).
As the exact exercise prescription is still a debate (intensity, frequency, and duration), researchers agree that physical activity provides benefits that outweigh any hormonal measurement.
All the former are risk factors for CVD which can be counteracted through both vigorous and non vigorous activity. For example, after 6 months of training, a low-volume moderate intensity group improved insulin sensitivity by 40%, whereas a high volume/high intensity group improved by 85% (29). Therefore, epidemiological evidence reported in the literature shows that physical activity is inversely and causally related to the incidence of CVD. Moreover, previous studies demonstrate that physical activity enhances whole body insulin sensitivity, resulting in enhanced muscle glucose uptake in both healthy and obese, insulin resistant animals and humans (31, 32, 33, 34). It is important to note however, that exercise/physical activity not only is advantageous towards hormone concentrations, body mass, and macronutrient profiles, but is beneficial to the heart as well. This is through the up regulation of the inducible Hsp70 (50).
EXERCISE IS A FORM OF STRESS
WHAT?! Exercise is a form of stress…this whole time health advocates have been saying it is a good tool to use for de-stressing the body and that it is good for you. Well, yes as a matter of fact it does all of the latter, however, metabolically it is a form of stress. That is why if someone is ill, or already has some type of physiological disorders (overtrained, adrenal fatigue, etc.) you would want to do low intensity, more parasympathetic dominant exercises so you are not putting your body into overdrive; exhausting and stressing the system.
An important function of the body is to maintain homeostasis in order for the organs, tissues, and systems to function optimally. This in turn results in fewer illnesses, and diseases, as these appear when the body is unable to maintain homeostasis in a certain localized area/vasculature. Regardless of the benefits of physical activity, it causes the body to shift from a homeostatic state. Moreover, muscles are being damaged, and depending on the intensity of exercise, metabolic accumulation can cause enzymes to not function optimally. During exercise, the body’s ionic concentration changes, thereby affecting the sodium-potassium ATPase Pump. There is also an increase in metabolites (e.g., lactate, adenosine diphosphate, inorganic phosphate, magnesium, and reactive oxygen species), and a decrease in the high energy metabolite, adenosine triphosphate. All of this is accompanied by an elevated core temperature and oxidative damage.
Skeletal muscle adapts to this shift from homeostasis through the up regulation of heat shock proteins (HSP); which play an important role in cell maintenance and protein survival. The focus of this review will be on the inducible Hsp70, which received its name based on its molecular weight of 70-kD. This increase in HSP has not only shown to be beneficial to the cardiovascular system, but to the musculoskeletal system as well.
However, there seems to be a sex difference both in the potential benefits of exercise and the up regulation of HSP. For example, after performing short term (6 weeks) endurance training, females did not respond to continuous or interval training in terms of increasing HSP content. However, males were able to increase HSP levels through both forms of training (45). Therefore, it is evident that females may need to work at a greater intensity and/ or duration than their male counterparts, and may have a conflicting variable or hormone that inhibits this increase in HSP.
This is only part one, there is much more to this topic and I hope many of you readers are still with me. Feel free to ask any questions if you need clarification in the comments section. In part two, I will dig deeper in this cardio protective protein named Hsp70.
Nadine is a talented fitness model, trainer and nutrition expert who also holds a Masters Degree in Exercise Physiology from the University of Windsor. Her research specialty is glucose handling in Type 2 diabetics during high intensity interval exercise (HITT). Nadine also holds a B.S. in Kinesiology from the University of Windsor. In addition, Nadine is a certified strength coach under Charles Poliquin, a certified Biosignature Practitioner through Charles Poliquin, and a certified nutritional consultant through Precision Nutrition.
Nadine’s personal philosophy is to challenge people beyond what they believe they are capable of accomplishing. She hopes to inspire people to adapt to a healthier lifestyle. She believes people not only need to change their mindset towards exercise, but must also have a positive and balanced relationship with food. She truly believes a healthy mind represents a healthy body. For nutrition consultation or personal training, you can contact Nadine at firstname.lastname@example.org.
1. The prevalence and costs of diabetes [Online]. 2009.
2. Ahmed-Sorour H and Bailey CJ. Role of ovarian hormones in the long-term control of glucose homeostasis, glycogen formation and gluconeogenesis. Ann Nutr Metab 25: 208-212, 1981.
3. Allen DG, Lamb GD and Westerblad H. Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88: 287-332, 2008.
4. Barrett-Connor E. Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation 95: 252-264, 1997.
5. Bassuk SS and Manson JE. Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease. J Appl Physiol 99: 1193-1204, 2005.
6. Beato M and Klug J. Steroid hormone receptors: an update. Hum Reprod Update 6: 225-236, 2000.
7. Benjamin IJ and McMillan DR. Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. Circ Res 83: 117-132, 1998.
8. Benjamin IJ and McMillan DR. Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. Circ Res 83: 117-132, 1998.
9. Billat LV. Interval training for performance: a scientific and empirical practice. Special recommendations for middle- and long-distance running. Part I: aerobic interval training. Sports Med 31: 13-31, 2001.
10. Brown DA, Jew KN, Sparagna GC, Musch TI and Moore RL. Exercise training preserves coronary flow and reduces infarct size after ischemia-reperfusion in rat heart. J Appl Physiol 95: 2510-2518, 2003.
11. Brown DA, Lynch JM, Armstrong CJ, Caruso NM, Ehlers LB, Johnson MS and Moore RL. Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. J Physiol 564: 619-630, 2005.
12. Chicco AJ, Schneider CM and Hayward R. Voluntary exercise protects against acute doxorubicin cardiotoxicity in the isolated perfused rat heart. Am J Physiol Regul Integr Comp Physiol 289: R424-R431, 2005.
13. Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A and Febbraio MA. HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A 105: 1739-1744, 2008.
14. Collins P, Rosano GM, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG and Poole-Wilson PA. 17 beta-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation 92: 24-30, 1995.
15. Craig EA. The heat shock response. CRC Crit Rev Biochem 18: 239-280, 1985.
16. Donnelly TJ, Sievers RE, Vissern FL, Welch WJ and Wolfe CL. Heat shock protein induction in rat hearts. A role for improved myocardial salvage after ischemia and reperfusion? Circulation 85: 769-778, 1992.
17. Egan JJ, Greenberg AS, Chang MK and Londos C. Control of endogenous phosphorylation of the major cAMP-dependent protein kinase substrate in adipocytes by insulin and beta-adrenergic stimulation. J Biol Chem 265: 18769-18775, 1990.
18. Elks ML and Manganiello VC. Antilipolytic action of insulin: role of cAMP phosphodiesterase activation. Endocrinology 116: 2119-2121, 1985.
19. Ellis RJ and van der Vies SM. Molecular chaperones. Annu Rev Biochem 60: 321-347, 1991.
20. Friedman MM. Gender differences in the health related quality of life of older adults with heart failure. Heart Lung 32: 320-327, 2003.
21. Fritz T, Wandell P, Aberg H and Engfeldt P. Walking for exercise–does three times per week influence risk factors in type 2 diabetes? Diabetes Res Clin Pract 71: 21-27, 2006.
22. Gething MJ and Sambrook J. Protein folding in the cell. Nature 355: 33-45, 1992.
23. Gornik I, Vujaklija A, Lukic E, Madzarac G and Gasparovic V. Hyperglycaemia in critical illness is a risk factor for later development of type II diabetes mellitus. Acta Diabetol 2009.
24. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL and Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 117: 1016-1037, 1992.
25. Gupte AA, Bomhoff GL, Swerdlow RH and Geiger PC. Heat treatment improves glucose tolerance and prevents skeletal muscle insulin resistance in rats fed a high-fat diet. Diabetes 58: 567-578, 2009.
26. Hammond GL, Lai YK and Markert CL. Diverse forms of stress lead to new patterns of gene expression through a common and essential metabolic pathway. Proc Natl Acad Sci U S A 79: 3485-3488, 1982.
27. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M and Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 420: 333-336, 2002.
28. Hotamisligil GS. Inflammation and metabolic disorders. Nature 444: 860-867, 2006.
29. Houmard JA, Tanner CJ, Slentz CA, Duscha BD, McCartney JS and Kraus WE. Effect of the volume and intensity of exercise training on insulin sensitivity. J Appl Physiol 96: 101-106, 2004.
30. Hsieh YC, Yu HP, Frink M, Suzuki T, Choudhry MA, Schwacha MG and Chaudry IH. G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma-hemorrhage. Am J Pathol 170: 1210-1218, 2007.
31. Knowlton AA, Kapadia S, Torre-Amione G, Durand JB, Bies R, Young J and Mann DL. Differential expression of heat shock proteins in normal and failing human hearts. J Mol Cell Cardiol 30: 811-818, 1998.
32. Knowlton AA and Sun L. Heat-shock factor-1, steroid hormones, and regulation of heat-shock protein expression in the heart. Am J Physiol Heart Circ Physiol 280: H455-H464, 2001.
33. Kosztin D, Bishop TC and Schulten K. Binding of the estrogen receptor to DNA. The role of waters. Biophys J 73: 557-570, 1997.
34. Kulhanek-Heinze S, Gerbes AL, Gerwig T, Vollmar AM and Kiemer AK. Protein kinase A dependent signalling mediates anti-apoptotic effects of the atrial natriuretic peptide in ischemic livers. J Hepatol 41: 414-420, 2004.
35. Lindquist S and Craig EA. The heat-shock proteins. Annu Rev Genet 22: 631-677, 1988.
36. Lindquist S and Craig EA. The heat-shock proteins. Annu Rev Genet 22: 631-677, 1988.
37. Londos C, Honnor RC and Dhillon GS. cAMP-dependent protein kinase and lipolysis in rat adipocytes. III. Multiple modes of insulin regulation of lipolysis and regulation of insulin responses by adenylate cyclase regulators. J Biol Chem 260: 15139-15145, 1985.
38. Marber MS, Latchman DS, Walker JM and Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88: 1264-1272, 1993.
39. Marber MS, Mestril R, Chi SH, Sayen MR, Yellon DM and Dillmann WH. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 95: 1446-1456, 1995.
40. McGrath LB, Locke M, Cane M, Chen C and Ianuzzo CD. Heat shock protein (HSP 72) expression in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 109: 370-376, 1995.
41. Melling CW, Thorp DB and Noble EG. Regulation of myocardial heat shock protein 70 gene expression following exercise. J Mol Cell Cardiol 37: 847-855, 2004.
42. Mendelsohn ME and Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 340: 1801-1811, 1999.
43. Moncada S and Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 329: 2002-2012, 1993.
44. Morales DE, McGowan KA, Grant DS, Maheshwari S, Bhartiya D, Cid MC, Kleinman HK and Schnaper HW. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91: 755-763, 1995.
45. Morton JP, Holloway K, Woods P, Cable NT, Burniston J, Evans L, Kayani AC and McArdle A. Exercise training-induced gender-specific heat shock protein adaptations in human skeletal muscle. Muscle Nerve 39: 230-233, 2009.
46. Morton JP, MacLaren DP, Cable NT, Bongers T, Griffiths RD, Campbell IT, Evans L, Kayani A, McArdle A and Drust B. Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging treadmill exercise. J Appl Physiol 101: 176-182, 2006.
47. Nakano M, Mann DL and Knowlton AA. Blocking the endogenous increase in HSP 72 increases susceptibility to hypoxia and reoxygenation in isolated adult feline cardiocytes. Circulation 95: 1523-1531, 1997.
48. Nilsson S and Gustafsson JA. Biological role of estrogen and estrogen receptors. Crit Rev Biochem Mol Biol 37: 1-28, 2002.
49. Paroo Z, Dipchand ES and Noble EG. Estrogen attenuates postexercise HSP70 expression in skeletal muscle. Am J Physiol Cell Physiol 282: C245-C251, 2002.
50. Paroo Z, Haist JV, Karmazyn M and Noble EG. Exercise improves postischemic cardiac function in males but not females: consequences of a novel sex-specific heat shock protein 70 response. Circ Res 90: 911-917, 2002.
51. Patten RD, Pourati I, Aronovitz MJ, Baur J, Celestin F, Chen X, Michael A, Haq S, Nuedling S, Grohe C, Force T, Mendelsohn ME and Karas RH. 17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling. Circ Res 95: 692-699, 2004.
52. Plumier JC, Ross BM, Currie RW, Angelidis CE, Kazlaris H, Kollias G and Pagoulatos GN. Transgenic mice expressing the human heat shock protein 70 have improved post-ischemic myocardial recovery. J Clin Invest 95: 1854-1860, 1995.
53. Powell KE, Thompson PD, Caspersen CJ and Kendrick JS. Physical activity and the incidence of coronary heart disease. Annu Rev Public Health 8: 253-287, 1987.
54. Radford NB, Fina M, Benjamin IJ, Moreadith RW, Graves KH, Zhao P, Gavva S, Wiethoff A, Sherry AD, Malloy CR and Williams RS. Cardioprotective effects of 70-kDa heat shock protein in transgenic mice. Proc Natl Acad Sci U S A 93: 2339-2342, 1996.
55. Ranki HJ, Budas GR, Crawford RM, Davies AM and Jovanovic A. 17Beta-estradiol regulates expression of K(ATP) channels in heart-derived H9c2 cells. J Am Coll Cardiol 40: 367-374, 2002.
56. Richard D, Rochon L and Deshaies Y. Effects of exercise training on energy balance of ovariectomized rats. Am J Physiol 253: R740-R745, 1987.
57. Saengsirisuwan V, Pongseeda S, Prasannarong M, Vichaiwong K and Toskulkao C. Modulation of insulin resistance in ovariectomized rats by endurance exercise training and estrogen replacement. Metabolism 58: 38-47, 2009.
58. Saltin B, Nazar K, Costill DL, Stein E, Jansson E, Essen B and Gollnick D. The nature of the training response; peripheral and central adaptations of one-legged exercise. Acta Physiol Scand 96: 289-305, 1976.
59. Shinohara T, Takahashi N, Ooie T, Ichinose M, Hara M, Yonemochi H, Saikawa T and Yoshimatsu H. Estrogen inhibits hyperthermia-induced expression of heat-shock protein 72 and cardioprotection against ischemia/reperfusion injury in female rat heart. J Mol Cell Cardiol 37: 1053-1061, 2004.
60. Sillanpaa E, Laaksonen DE, Hakkinen A, Karavirta L, Jensen B, Kraemer WJ, Nyman K and Hakkinen K. Body composition, fitness, and metabolic health during strength and endurance training and their combination in middle-aged and older women. Eur J Appl Physiol 2009.
61. Smith J and Mc NL. The effects of intensity of exercise on excess postexercise oxygen consumption and energy expenditure in moderately trained men and women. Eur J Appl Physiol Occup Physiol 67: 420-425, 1993.
62. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE and Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med 325: 756-762, 1991.
63. Stevenson JC. HRT and cardiovascular disease. Best Pract Res Clin Obstet Gynaecol 23: 109-120, 2009.
64. Sugden PH and Bogoyevitch MA. Intracellular signalling through protein kinases in the heart. Cardiovasc Res 30: 478-492, 1995.
65. Sugioka K, Shimosegawa Y and Nakano M. Estrogens as natural antioxidants of membrane phospholipid peroxidation. FEBS Lett 210: 37-39, 1987.
66. Taylor RP, Harris MB and Starnes JW. Acute exercise can improve cardioprotection without increasing heat shock protein content. Am J Physiol 276: H1098-H1102, 1999.
67. Thawornkaiwong A, Preawnim S and Wattanapermpool J. Upregulation of beta 1-adrenergic receptors in ovariectomized rat hearts. Life Sci 72: 1813-1824, 2003.
68. Thorp DB, Haist JV, Leppard J, Milne KJ, Karmazyn M and Noble EG. Exercise training improves myocardial tolerance to ischemia in male but not in female rats. Am J Physiol Regul Integr Comp Physiol 293: R363-R371, 2007.
69. Vaccarino V, Lin ZQ, Kasl SV, Mattera JA, Roumanis SA, Abramson JL and Krumholz HM. Sex differences in health status after coronary artery bypass surgery. Circulation 108: 2642-2647, 2003.
70. Vaccarino V, Parsons L, Every NR, Barron HV and Krumholz HM. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 341: 217-225, 1999.
71. Voss MR, Stallone JN, Li M, Cornelussen RN, Knuefermann P and Knowlton AA. Gender differences in the expression of heat shock proteins: the effect of estrogen. Am J Physiol Heart Circ Physiol 285: H687-H692, 2003.
72. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V and Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 325: 1196-1204, 1991.
73. Wellen KE and Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 115: 1111-1119, 2005.
74. Xiao X and Benjamin IJ. Stress-response proteins in cardiovascular disease. Am J Hum Genet 64: 685-690, 1999.
75. Zugel U and Kaufmann SH. Role of heat shock proteins in protection from and pathogenesis of infectious diseases. Clin Microbiol Rev 12: 19-39, 1999.