Horm Mol Biol Clin Invest 2015; 21(2): 117–124

Christiane Habich and Henrike Sell*

Heat shock proteins in obesity: links to cardiovascular disease Abstract: Adipose tissue expansion is associated with adipocyte dysfunction and increased inflammatory processes. In the obese state, adipose tissue is characterized by an impaired intracellular stress defense system and dysbalanced heat shock response. Several members of the heat shock protein (HSP) family have been identified as novel adipokines released upon cellular stress, which might be a molecular link from adipose tissue inflammation to the cardiovascular system. Therefore, this review aims at summarizing and discussing our recent knowledge on HSPs in relation to obesity and their potential links to cardiovascular disease. Of particular importance/ interest are two members of the HSP family, HSP60 and heme oxygenase 1 (HO-1), which have been well described as adipokines, and studied in the context of obesity and cardiovascular disease. HSP60 is regarded as a novel molecular link between adipose tissue inflammation and obesity-associated insulin resistance. The role of HO-1 induction in the obese state is well-documented, but a causal relationship between increased HO-1 levels and obesity-associated metabolic diseases is still controversial. Both HSP60 and HO-1 are also forthcoming targets for the treatment of cardiovascular disease, and the current knowledge will also be discussed in this review. Keywords: adipokine; adipose tissue; cardiovascular disease; heat shock protein; HO-1; HSP60; inflammation; obesity. DOI 10.1515/hmbci-2014-0040 Received November 10, 2014; accepted January 28, 2015

*Corresponding author: Henrike Sell, Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center, Auf’m Hennekamp 65, D-40225 Düsseldorf, Germany, Phone: +49 211 3382622, Fax: +49 211 3382697, E-mail: [email protected] Christiane Habich: German Diabetes Center, Düsseldorf, Germany

Introduction Expansion of adipose tissue is associated with various aspects of adipose tissue dysfunction, including increased inflammation, changes in tissue oxygen tension, fibrosis, and cellular stress in general [1]. Adipose tissue dysfunction is not only a local phenomenon but also tangible in the periphery where in serum a dysbalance of pro- and anti-inflammatory adipokines can be measured. We and others have contributed to the identification of innumberable adipokines that might serve as molecular links between expanded adipose tissue and other organs, including the vascular system [2]. In the last year, several members of the heat shock protein family have been identified as novel adipokines released upon cellular stress from adipocytes in vitro and potentially also in vivo. In the obese state, organs that play a central role in energy metabolism, including skeletal muscle, liver and adipose tissue, are also characterized by an impaired intracellular stress defense system [3]. In this context, the impairment of the overall stress response is highly complex, including a dysbalance of the heat shock response (HSR), in addition to mitochondrial dysfunction, uncontrolled oxidative, and endoplasmic reticulum (ER) stress. HSR is a crucial cellular tool to cope with different stressors, including heat, cold, and metabolic stress [4]. The most important components of this response are the highly conserved proteins from different HSP families, which are also known as molecular chaperones, glucoseregulated proteins, and proteins essential for protection and recovery from tissue damage [5]. Intracellularly, HSPs bind to misfolded, aggregated, and nascent proteins where they assist in proper folding, dissolving, or translocation. In addition, HSPs eliminate damaged or dysfunctional proteins for degradation. An increasing number of reports also describe the release of HSPs from intact cells, including adipocytes, immune, and vascular cells to the circulation [6, 7]. Extracellularly, HSPs are binding partners and ligands for Toll-like receptors, thereby activating inflammatory processes [8]. Several families of HSPs classified according to their molecular weight and functionality are identified, including small HSPs, HSP27, HSP60, HSP70, and HSP90. Recent

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118      Habich and Sell: Heat shock proteins in obesity data indicate that adipose tissue is a source of various HSPs, which are of interest for obesity research, as HSPs are potential mediators of adipose tissue inflammation and its metabolic consequences. This review aims at summarizing and discussing our recent knowledge on HSPs in relation to obesity. As both HSP60 and heme oxygenase 1 (HO-1) are particularly well-studied, part of the review is focused on these candidates. The roles of HSP60 and HO-1 in cardiovascular disease are becoming clear, and will be discussed for their potential to be targeted for the treatment of cardiovascular disease.

HSPs and obesity Although numerous HSPs have been identified as adipokines [2], only a few studies have analyzed the regulation and possible additional functions of HSPs in adipocytes and in adipose tissue. One of the first observations on HSPs in adipose tissue, dating back to the 1970s, was the cold induction of HSP70 in brown adipocytes [9, 10]. Cold-induced expression of HSP70 is not restricted to brown adipose tissue but occurs in parallel in vessels depending on alpha1-adrenergic antagonism. Mechanistically, noradrenalin as a mediator of non-shivering thermogensis is able to induce HSP70 in brown adipocytes potentially via a nitric oxide (NO)-dependent pathway [11]. As a protective mechanism, HSP70 induction prevents tumor necrosis factor (TNF)α-induced apoptosis in brown adipose tissue. In addition, N-acetylcystein, as an anti-oxidant, reduces HSP70 expression in murine 3T3-L1 adipocytes [12]. Interestingly, the cold-induced regulation of HSP70 is defective in the context of type 2 diabetes in mice [13].

Findings from human studies Several HSPs show altered regulation in the obese state in rodents and humans. One of the most comprehensive analyses demonstrated the up-regulation of protein levels of HSP60, HSP72, HSP90, HSC70, and GRP94 in obese patients compared with lean patients [14]. Only DnaJ (Hsp40) homolog, subfamily B, member 3 (DNAJB3) was downregulated in the obese state, which was also corroborated by another study [15]. Interestingly, the same study also evaluated expression levels of these candidates after exercise intervention in obese subjects. That study found a clear increase in DNAJB3 in obese exercising patients while all other HSPs were downregulated in parallel. In

addition to adipose tissue, a similar regulation by exercise was measured in peripheral blood mononuclear cells (PBMCs), indicating that there was no restriction to adipose tissue. The fact that the studied obese group was still insulin sensitive despite having an already defective HSR indicated that a dysregulation of this stress response may have occurred prior to insulin resistance. However, in numerous other studies, it was suggested that the HSR could play a role in the development of insulin resistance although a causal relationship is still to be fully established and might involve different tissues at different time points in the development of metabolic complications [3]. The regulation of HSPs also occurs in relation to obesity-associated metabolic diseases, which is the case for HSP27, for example. This HSP is specifically decreased in adipose tissue of women with gestational diabetes compared to controls [16]. As maternal adipose tissue plays a central role in the pathophysiology of gestational diabetes and HSP27 is involved in contractions, an altered HSR may be involved in inflammation of visceral adipose tissue and contribute to metabolic abnormalities during pregnancy. A few studies also related HSP serum concentrations and HSP antibodies to obesity. For instance, serum HSP70 is significantly lower in obese patients, while HSP90 remains unchanged. Serum HSP70 correlated negatively with body mass index (BMI), waist, body fat and homeostasis model assessment (HOMA) [17]. HSP27 antibody titers are higher in obese but healthy subjects compared to lean controls, which might indicate increased immunoactivation. In a cross-sectional study involving only healthy subjects, HSP27 antibody titer correlated with BMI [18]. In addition to HSP27, increased titers of HSP60, HSP65, and HSP70 antibodies can also be measured in obese subjects [19].

Insights from animal models The regulation of a few HSPs has also been investigated in rodent models of stress and obesity. Chronic stress augments HSP70 expression in adipose tissue in mice, which are additionally characterized by smaller adipocytes and less body fat, but higher inflammation and glucose intolerance [20]. Acute stress and exercise have been shown to increase HSP72 in adipose tissue and serum of rats [21]. Interestingly, wheel running training of rats previous to acute stress led to a further increase in HSP72 parallel to reduced responses of TNFα and interleukin 1β (IL-1β) indicative for a specific modulation of adipose tissue inflammation. In line with this observation, HSP72 is decreased by a high-fat diet in female rats [22]. In contrast

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Habich and Sell: Heat shock proteins in obesity      119

to HSP72, HSP27 is upregulated in adipose tissue by dietinduced obesity in rats, which can be prevented by Capsaicin treatment (another inducer of thermogenesis) [23]. Genetic manipulation of different HSPs in rodent models is also related to the development of obesity and associated metabolic diseases. In Sec61a1 mutant mice that develop non-alcoholic liver disease, increased HSP90 expression stimulates peroxisome proliferator-activated receptor (PPAR)γ protein levels and signaling, leading to increased lipid accumulation [24]. This function of HSP90 might also be relevant for lipid accumulation in enlarging adipocytes – an interesting topic for further research. Ubiquitous overexpression of HSP72 in the whole animal or targeted only in skeletal muscle has been found to prevent diet-induced obesity [25, 26]. Mechanistically, HSP72 stimulates fat oxidation in skeletal muscle, following reduction in fat storage and adiposity. Accordingly, HSP72 expression in skeletal muscle is related to obesity. However, no regulation of HSP72 can be observed in adipose tissue in mice [27], which is different from the human situation [14]. Similar to genetic manipulation, geranylgeranylacetone, an antioxidant and phytoprotective agent, induces HSP72, mainly in the liver and brown adipose tissue, as well as prevents visceral adiposity and its complications [28]. Thus, HSP72 in skeletal muscle, liver, and brown adipose tissue is related to higher energy expenditure preventing obesity. However, the role of HSP72 within adipose tissue remains unclear.

The physiological signals triggering the secretion of proinflammatory mediators from adipocytes in the obese state remain largely unknown; hence, HSP60 is an interesting candidate in this context. This is particularly relevant in the setting of obesity-associated metabolic diseases, such as insulin resistance, type 2 diabetes, and cardiovascular disease. For instance, HSP60 is able to induce insulin resistance in skeletal muscle cells where it also triggers release of pro-inflammatory myokines [29]. Interestingly, HSP60 expression is particularly high in visceral adipose tissue from obese patients with the metabolic syndrome [29], and HSP60 serum concentrations are also elevated in type 2 diabetic subjects [34]. Overall, HSP60 can be regarded as a novel molecular link between adipose tissue inflammation and obesity-associated metabolic diseases (Figure 1). Nevertheless, further research on HSP60 as a potentially therapeutic target is required in the future.

Role of Hsp60 in obesity One of the most studied HSPs in adipose tissue and adipocytes is HSP60 [9, 10]. While we could not find a differentiation-dependent regulation of HSP60 in human adipocytes [29], another study found an up-regulation of HSP60 along with regulation of other HSPs in adipocytes [30]. HSP60 can be considered a real adipokine because this HSP is released from adipocytes in measurable amounts, which increase over differentiation despite similar protein abundance in the cell. Interestingly, freshly isolated stromavascular cell fractions express less HSP60 than isolated mature adipocytes, indicating that in vivo HSP60 is more abundant in differentiated fat cells [29]. Such data are further supported by the observation that obese individuals are characterized by higher circulating HSP60 levels. HSP60 can be regulated in adipocytes by inflammatory stress signals, such as lipopolysaccharide (LPS), IL-1β and TNFα [29]. Conversely, HSP60 treatment induces the release of pro-inflammatory cytokines and adipokines from murine and human adipocytes [29, 31–33].

Inflammatory and/or metabolic stress

Up-regulation of HSPs (e.g. Hsp60) expression and/or release into the circulation

Induction and release of inflammatory mediators

Contribution to tissue inflammation

Metabolic and cardiovascular diseases

Figure 1: Role of HSPs in obesity and cardiovascular diseases.

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Role of HO-1 in adipose tissue HO-1, as a member of the 40 kD HSPs, has recently attracted considerable attention due to its unexpected and still controversial role in the development of obesity and insulin resistance in humans and mice. Both, HO-1 and HO-2 catalyze the conversion of heme into biliverdin, carbon monoxide, and ferrous iron. The constitutive isoform HO-2 as well as the inducible isoform HO-1 are expressed ubiquitously. The HO-1 isoform can be induced by various stimuli, including hypoxia, toxin exposure, inflammation, and tissue injury. The products of heme catabolism, biliverdin, and carbon monoxide all have additional important functions in the cardiovascular systems. Our group was the first to describe HO-1 as an adipokine in 2011 by a proteomic analysis of the secretome of human adipocytes [35]. Basal characterization of this factor revealed a solid upregulation of HO-1 expression and secretion from in vitro differentiated adipocytes. In humans, HO-1 is higher in serum and in both subcutaneous and visceral adipose tissues of obese subjects compared with lean ones. In addition, HO-1 serum concentrations correlate with adipocyte size measured in adipose tissue biopsies. Other studies have found similar induction of HO-1 in adipose tissue in obesity [36, 37]. However, conflicting results concerning expression of HO-1 in visceral adipose tissue in relation to insulin sensitivity in obese patients have also been published. For example, one study observed the decreased expression of HO-1 with increasing waist-hip-ratio (WHR) as a marker of risk for the metabolic syndrome [37]. Another study clearly demonstrated increased HO-1 expression, particularly in insulin-resistant obese patients with increased WHR compared to insulin-sensitive obese controls [36]. This issue needs further validation. In vitro, HO-1 is involved in adipogenesis, as supported by the observation that induction of HO-1 by cobalt protoporphyrin IX (CoPP) decreases lipid accumulation and differentiation marker in previous studies [38–40]. HO-1 induction by CoPP changes the appearance of adipocytes from cells with large lipid droplets secreting high amounts of pro-inflammatory adipokines and lower amounts of adiponectin to adipocytes; meanwhile, smaller lipid droplets secreting lower amounts of pro-inflammatory adipokines and higher amounts of adiponectin. After HO-1 induction, several pathways are upregulated, including AMP-activated protein kinase (AMPK) activation and PPARγ activation. Genetic manipulation of HO-1 in rodents was performed using different approaches, such as knockdown, overexpression and targeted deletion in single organs,

resulting in conflicting data. HO-1 knockdown in mice is associated with significantly increased perinatal death and susceptibility to inflammation [41]. Lentiviral HO-1 overexpression targeted to adipocytes reduces obesity and vascular dysfunction in diet-induced obese mice [42]. Another study that induced human HO-1 driven by the adipocyte Protein 2 (aP2) promotor in mice showed that it had no influence on obesity and obesity-associated metabolic dysfunction [43]. Mice with myeloid-specific haploinsufficiency in HO-1 are protected from insulin resistance induced by high-fat feeding associated with depressed macrophage infiltration in adipose tissue [44]. This study was corroborated by a recent publication with macrophage-specific HO-1 depletion, which observed a modulation of adipose tissue inflammation in parallel to resistance to obesity-associated insulin resistance and liver steatosis [36]. The same authors also demonstrated that liver-specific knockout of HO-1 are hypersensitive to insulin and are protected from hepatosteatosis after highfat diet challenge. Meanwhile, several research groups have s­ uccessfully tested the HO-1 inducer CoPP and hemin in different metabolic challenges in rodents. CoPP was administered to ob/ob mice and Zucker obese rats and was found to decrease weight gain, fat mass accumulation, and adipose tissue inflammation [45–47]. Differently, hemin administration did not affect body weight development in GotoKakizaki rats and Sprague-Dawley, but significantly lowered fasting and postprandial blood glucose concentrations [48]. Interestingly, adiponectin serum concentrations have been found to significantly increase, particularly in the diabetic rat model, despite unchanged body weight and adiposity. The upregulation of adiponectin by HO-1 induction has also been suggested by several other studies as a mechanism underlying the beneficial metabolic and cardiovascular effects of CoPP. In summary, the role of HO-1 induction in the obese state is well-documented, but a causal relationship between increased HO-1 and obesityassociated metabolic diseases has yet to be clearly established. Future research is needed to clarify whether HO-1 induction or HO-1 inhibition are therapeutic strategies to combat obesity-associated metabolic diseases.

Links to cardiovascular diseases Physiologically, HSPs play a protective role in various tissues and in the homeostasis of the cardiovascular system. However, in pathological conditions, HSPs have been shown to modulate inflammatory processes involved

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in the development of cardiovascular diseases, such as atherosclerosis. Growing evidence suggests that several HSPs are involved in the pathogenesis of cardiovascular disease, which has been reviewed by experts of the field [49, 50]. Due to the authors’ selection of HSP60 and HO-1 as interesting candidates from the HSP family in relation to obesity and obesity-associated metabolic diseases, we will also focus on HSP60 and HO-1 as HSPs that are relevant to the development of cardiovascular diseases. The link between HSP60 and cardiovascular disease has been known for many years [51]. HSP60 is a mitochondrial chaperone that has also been found extramitochondrially and extracellularly. Under normal physiological conditions, HSP60 is mainly localized in mitochondria and in the cytosol and has been found to be membraneassociated to a certain extent. HSP60 exerts its cytoprotective effects whether intracellularly or membrane-bound. Under various forms of stress, however, HSP60 can be converted into a harmful molecule. Whether HSP60 is protective or harmful is related to its location. When HSP60 is released outside the cell, it is primarily an indication of cellular death and activates the immune system for clearance of debris. For example, in hypoxic cardiomyocytes, cytosolic HSP60 is reduced, while more HSP60 is shifted to the membrane and released in the form of exosomes, as reviewed in [52]. In fact, exosomes released from cardiomyocytes have been shown to contain HSP60 [6]. Extracellular HSP60 may be apoptosis-inducing to other cardiomyocytes, potentially due to the activation of Tolllike receptor 4 [53]. It can be envisaged that HSP60 released from still intact cells can also induce cellular stress and activate inflammation in other organs, which could be the case for adipose tissue in obesity. When higher amounts of HSP60 are released from enlarged adipocytes, this HSP could induce or maintain inflammation of adipose tissue. Increased HSP60 levels in the circulation of obese patients can also reach and stimulate endothelial cells, other cells in the vascular wall, and the myocardium. The precise molecular effects of HSP60 in the cardiovascular system have been reviewed in previous works [50, 52, 54]. From a clinical perspective, measurements of HSP60 concentrations, specifically in exosomes, offer a promising tool in diagnostics and monitoring of disease progression in both obesity and cardiovascular diseases [55]. Furthermore, vaccination with HSP60 peptides has been tested for other indications, such as type 1 diabetes and cancer. However, this approach might be translated to patients with cardiovascular disease and obese patients with a higher risk for cardiovascular complications. HO-1 is a relatively novel target for the treatment of cardiovascular diseases. HO-1 expression in humans is

exteremely variable due to a highly polymorphic promoter. The resulting variability in HO-1 levels is clinically relevant because HO-1 abundance correlates with the risk of cardiovascular disorders [56]. As the rate-limiting enzyme degrading heme, it also releases bioactive molecules that, in turn, exert cardiovascular-protective actions [56]. Similar to NO, carbon monoxide works as a vasodilator that reduces inflammation via mitogen-activated protein kinase (MAPK) signaling [57]. Furthermore, this product of HO-1 exerts anti-apoptotic effects on endothelial cells and anti-proliferative effects in vascular smooth muscle cells. Biliverdin is rapidly converted into bilirubin, and both substances display anti-inflammatory properties and functions as potent antioxidants, free radical scavengers, and inhibitors of the complement cascade [58]. Clinically, HO-1 is related to atherosclerosis, hypertension, myocardial infarction and stroke, all of which are highly related to obesity [56]. Accumulated data suggest that the protective effect of HO-1 in atherosclerosis is mediated by its anti-inflammatory action in the vascular wall [59]. Hypertension, as a major cause of atherosclerosis, is also tightly linked with HO-1 expression and activity [60]. HO-1 is elevated in animals with induced hypertension. Conversely, induction or overexpression of HO-1 reduces the blood pressure while the inhibition of HO-1 causes hypertension in different rodent models. In the context of myocardial infarction, HO-1 prevents ischemia-reperfusion-induced dysfunction and apoptosis of cardiomyocytes. Here again, overexpression of HO-1 or chemical induction of HO-1 is protective in animal models of infarction, which reduces infarct size and prevents oxidative stress, inflammation and fibrosis, resulting in overall reduced mortality. In addition to experimental compounds specifically used to induce HO-1, such as hemin and CoPP, several drugs in clinical use have been shown to induce HO-1 in patients. Statins, probucol, nonsteroidal anti-inflammatory drugs or rapamycin, used for cholesterol-lowering, reduction of inflammation and immunosuppression, respectively, also target HO-1, which might add to their known modes of action. The contributions of HO-1 to the cardioprotective action of these drugs, however, require more detailed analysis. Taken together, regarding the existing data on mouse models with HO-1 manipulation in different organs, it should be envisaged to target HO-1 induction specifically to the cardiovascular system, because the role of HO-1 in liver and immune cells is not clear and potentially pro-inflammatory [36]. Whether HO-1 is pro- or anti-inflammatory has yet to be completely understood and should be addressed in additional animal models with tissue-specific knockdown or overexpression.

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Conclusion The obese state is not only characterized by adipose tissue inflammation, but also by an altered HSR involving different HSPs that are dysregulated. HSP60 is a model adipokine that is increased in adipose tissue in the obese state, where it contributes to inflammation and metabolic disturbances, such as insulin resistance. Aside from a potential role in the pathogenesis of obesity and its associated metabolic diseases, HSP60 also has potential as a biomarker. In fact, we have recently shown that HSP60 serum concentrations in morbidly obese patients are significantly correlated to established risk markers for cardiovascular disease, including ApoB/ApoA1 and cholesterol/ HDL ratios. In relation to cardiovascular disease, HSP60 is thus useful for diagnosis, prognosis, treatment, assessment of response to treatment, and even prevention [52]. HO-1 is another promising candidate, which is dysregulated in adipose tissue and other organs in the obese state, as well as in relation to cardiovascular disease. The pharmacological upregulation of HO-1 has proven efficacy for the treatment of cardiovascular disease in animal models. However, genetic manipulation of HO-1 abundance in different organs in rodents has generated conflicting data as regards the pro- or anti-inflammatory nature of HO-1. In summary, it will be a future challenge to specifically target the HSR system and single HSPs for the treatment of cellular stress-related diseases, including obesity-associated metabolic disorders and cardiovascular diseases.

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Heat shock proteins in obesity: links to cardiovascular disease.

Adipose tissue expansion is associated with adipocyte dysfunction and increased inflammatory processes. In the obese state, adipose tissue is characte...
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