Adiponectin: mechanisms and new therapeutic approaches for restoring diabetic heart sensitivity to ischemic post-conditioning

Abstract

Systemic inflammatory response following myocardial ischemia-reperfusion injury (IRI) to a specific organ may cause injuries. Ischemic post-conditioning (IPostC) has emerged as a promising method for myocardial protection against IRI both in experimental and in clinical settings. Enhancement of endogenous nitric oxide (NO) is one of the major mechanisms by which IPostC confers cardioprotection. However, the sensitivity of the diabetic heart to IPostC is impaired and the underlying mechanism is unknown. Adiponectin (APN) is an adipocyte-derived plasma protein with anti-diabetic and anti-inflammatory properties. Plasma levels of APN are decreased in obese subjects and in patients with type 2 diabetes. APN supplementation has been shown to increase NO production and attenuate myocardial IRI in normal (non-diabetic) animals. However, the effect of APN on myocardial injury in diabetic subjects, especially its potential in restoring the sensitivity of the diabetic heart to IPostC has not been investigated. In the current paper, we discussed the possible reasons why the myocardium of diabetic subjects loses sensitivity to IPostC and also highlighted the potential effectiveness and mechanism of APN in restoring IPostC cardioprotection in diabetes. This review proposes to conduct studies that may facilitate the development of novel and optimal therapies to enhance cardioprotection in patients with severe diseases such as diabetes.

Keywords

adiponectin / ischemic post-conditioning / ischemia reperfusion injury / diabetes

Introduction

Myocardial infarction is a major perioperative complication that is associated with significant morbidity and mortality, particularly in patients with diabetes [1]. Reperfusion therapies restore coronary flow, but may cause lethal tissue injury called “ischemia-reperfusion injury (IRI).” Existing myocardial reperfusion strategies such as percutaneous coronary intervention (PCI) when applied expeditiously, limit myocardial infarct size. However, despite this, significant 30-day mortality and morbidity remain after PCI [2].

Murry et al. [3] first described that brief episodes of ischemia and reperfusion given before prolonged ischemia protect the myocardium, a phenomenon referred to as ischemic preconditioning (IPC). Although effective, IPC requires access to the coronary vessels which is not feasible in the majority of cases. Subsequently, attention has been focused on modifying events occurring at the time of myocardial reperfusion (i.e., ischemic post-conditioning [4], IPostC). However, the sensitivity of the diabetic heart to IPostC is impaired and the underlying mechanism is unknown.

Adiponectin (APN) is an adipocyte-derived plasma protein with anti-diabetic and anti-inflammatory properties [5,6]. Plasma APN levels are decreased in obese subjects and in patients with type 2 diabetes [7,8]. APN supplementation has been shown to increase the production of nitric oxide (NO), an important molecule in cellular protection, and attenuate myocardial IRI in normal (non-diabetic) animals [9,10]. However, the effect of APN on myocardial injury in diabetic subjects, especially its potential in restoring the sensitivity of the diabetic heart to IPostC has not been investigated. In the current paper, we discussed the possible reasons why the myocardium of diabetic subjects loses sensitivity to IPostC and also highlighted the potential effectiveness and mechanism of APN in restoring IPostC cardioprotection in diabetes.

Multiple protective pathways in ischemic pre- and post-conditioning cardioprotection

The release of NO represents one of the most important defense mechanisms against myocardial IRI. Findings from recent studies implicate NO (likely from endothelial NO synthase, eNOS) as a necessary participant in the development of the clinically relevant protective phenotype of post-conditioning [11]. Both pre- and post-conditioning, whether achieved by ischemia or by pharmacological means, are generally perceived to protect via the activation of the reperfusion injury salvage kinase (RISK) pathway, which includes activation of phosphatidylinositol 3-kinase (PI3K) and kinases Akt and extracellular regulated kinase (Erk) at the time of reperfusion and subsequent activation of eNOS signaling [12]. The RISK pathway is considered to play a predominant role in preconditioning cardioprotection.

The tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine, is generally thought to contribute to myocardial dysfunction in myocardial IRI. However, TNF-α, at moderately elevated concentrations, can paradoxically initiate the activation of a novel and alternative protective pathway against myocardial IRI which have been termed survivor activating factor enhancement (SAFE) pathway [13]. This pathway requires the activation of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT-3) signaling and it can successfully lessen myocardial IRI at the time of reperfusion, independent of the activation of the RISK pathway [14].

Studies have shown that cross-talk may exist between the RISK and SAFE pathways. For example, opioids can induce cardioprotection via the activation of both JAK/STAT-3 and PI3K/Akt pathways and PI3K activation can lead to STAT-3 phosphorylation/activation [15]. The mechanism governing the interaction between these two important signaling pathways may be the formation of protein complexes and that STAT3 may contribute to the formation of the protein complexes by serving as an adaptor protein to link PI3K and Jak2 [15,16]. Although cross-talk may exist between these two pathways, it is obvious that the SAFE pathway can function independent of the RISK pathway since cardioprotection can be obtained with blockade of the RISK pathway [13]. Of note, JAK/STAT-3 activation was shown to play an essential role in IPC mediated late protection [17], while the RISK pathway is not essential for IPostC to confer cardioprotection [18]. In fact, cardioprotection by IPostC is lost in aged and STAT-3 deficient mice [19]. Therefore, the delineation of the SAFE pathway offers new potential to further limit reperfusion injury and serves as the critical mediator to IPostC cardioprotection.

Clinical problem: responsiveness of diabetic hearts to ischemic post-conditioning

Myocardial infarction is a major cause of sudden death in diabetes mellitus. Despite that IPC or IPostC has been proved to efficiently prevent myocardial IRI in non-diabetic subjects, its effectiveness in diabetes is diminished or compromised [20]. The mortality of diabetic patients with acute myocardial infarction was found to be 2-fold to 6-fold higher than that of non-diabetic patients even when the severity of myocardial infarction was comparable. Attenuation or diminishment of responsiveness to IPC- and IPostC-mediated cardioprotection in diabetic condition should have exacerbated the pathology [20], while the underlying mechanism is largely unknown and merits further study.

Diabetes induced oxidative stress has been suggested to be the major mechanism contributing to the development and progression of myocardial infarction [21,22]. In the diabetic myocardium, NO availability is decreased despite increased myocardial inducible NO synthase (iNOS) expression [23,24], presumably due to increased peroxynitrite formation [25] and iNOS-dependent eNOS uncoupling [26], which may render the diabetic heart less sensitivity to IPC and IPostC.

Both IPC- and IPost-mediated myocardial protection is predominantly mediated by the RISK and/or SAFE pathway, while hyperglycemia has been shown to inhibit both the PI3K/Akt and Jak/STAT3 signaling [20]. Indeed, increasing evidence suggests that the RISK pathway and especially the SAFE pathway (which has been shown to be essential for IPostC to confer cardioprotection and can be activated independent of the RISK pathway [17,27]) are impaired in the diabetic myocardium. Therefore, the impairment of the JAK/STAT3 signaling [28] could be responsible for the loss of sensitivity to IPostC cardioprotection in diabetes.

Adiponectin in diabetes and its effect on myocardial ischemia reperfusion injury

Adiponectin (APN) is an adipocyte-derived plasma protein with anti-diabetic and anti-inflammatory properties [5,6]. It is mainly synthesized in white adipose tissue while lower concentrations are produced in brown adipose tissue [29]. Plasma APN levels are decreased in patients with type 2 diabetes [7] which was consistent with the result from a longitudinal study showing that the individuals with high APN levels were less likely to develop type 2 diabetes than those with low APN levels [30]. Our recent study also showed that both plasma and cardiac APN level was lower in streptozotocin-induced diabetic rats [8], and therapies that can enhance endogenous APN attenuated post-ischemic infarction in diabetes [8]. This finding suggests that APN may also play an important role in attenuating myocardial IRI in diabetes. However, whether or not APN may have the potential to restore diabetic heart responsesiveness to other therapeutic interventions such as IPostC is unknown and merits further exploration.

Increasing studies have shown that APN-knockout (APN-KO) mice develop increased myocardial damage and systolic dysfunction in response to ischemic insult, while APN supplementation increases NO production and attenuates myocardial IRI [9,10]. It has been shown that APN can induce eNOS action and increase NO production in human endothelial cells [31], and prevent diabetic premature senescence of endothelial progenitor cells and promote endothelial repair [32]. APN inhibits lipopolysaccharide-induced iNOS activation and the subsequently increased production of nitrotyrosine, a fingerprint of peroxynitrite in adventitial fibroblasts via APN receptor-1 (AdipoR1) mediated activation of AMP-activated protein kinase (AMPK) [33]. APN has also been shown to activate STAT-3 in adult mouse cardiac fibroblasts [34]. These properties of APN (i.e., activating STAT-3, enhancing NO production by eNOS, and inhibiting iNOS) may make APN supplementation an excellent therapy in attenuating myocardial IRI in diabetic subjects, in particular in restoring diabetic heart sensitivity to IPostC, given that activation of eNOS signaling via activation of STAT3 is a major mechanism of IPostC cardioprotection.

APN functions via its two receptors, namely APN receptor 1 (AdipoR1) and APN receptor 2 (AdipoR2). Interaction of AdipoR1/2 with an adaptor protein APPL1 is required for APN to induce NO production [31]. AMPK acts downstream of APPL1. AMPK phosphorylates/activates eNOS [35], but inhibits iNOS [33,36,37] and attenuates oxidative stress and cell death [38]. However, in contrast to its effects in non-diabetic rodents, IPostC failed to activate AMPK in diabetic hearts [39], presumably due to increased iNOS in the diabetic myocardium [25]. Thus, in diabetes, APN may act via AMPK to inhibit iNOS and activate eNOS to produce physiological levels of NO, leading to restoration of IPostC-induced cardioprotection. In addition to attenuate myocardial IRI via activation of AMPK, APN has also been shown to mediate cardioprotection against myocardial IRI via cyclooxygenase (COX)-2 dependent manners [9,40]. By activating COX-2, APN appears to be linked with prostaglandins, which themselves serve to protect various organs from ischemic insult [41]. However, COX-2 expression is increased in the myocardium of streptozocin (STZ)-induced type 1 diabetic rats [42]. Therefore, the potential importance of this pathway (i.e., adiponectin/COX-2 signaling) in diabetic myocardial protection merits further investigation.

APN has also been shown to activate STAT-3 in adult mouse cardiac fibroblasts [34]. It is yet to be determined whether or not APN can activate STAT-3 in cardiomyocytes. Studies have reported that eNOS/NO can enhance lipopolysaccharide-stimulated TNF-α expression in cardiomyocytes [43]. More importantly, there is evidence showing that NO is upstream of TNF-α formation, and TNF-α in turn activates STAT3, a key protein involved in pre- and post-conditioning cardioprotection [44,45]. TNF-α mediated activation of the SAFE pathway is essential for IPostC to confer cardioprotection. Based on these findings, we hypothesize that APN may activate the SAFE pathway by stimulating endothelial NO production, and subsequently stimulate (moderate level of) TNF-α production in cardiomyocytes.

Prospect and future direction

To our knowledge, currently all the studies regarding the effect or role of APN in myocardial IRI are performed in normal (i.e., non-diabetic) and in particular in APN gene knockout rodents [9,10,40]. Studies regarding whether or not APN can confer cardioprotection in diabetic rodents are lacking, although indirect evidence exists which shows that the beneficial effects of heme oxygenase-1 on myocardial IRI in diabetic rats involve an increase in APN [46].

Based on these findings, we propose that APN supplementation, through activating JAK/STAT-3 signaling pathway and enhancing NO content in the diabetic myocardium, should restore the sensitivity of the diabetic heart to IPostC. As illustrated in Fig. 1, TNF-α at low concentrations binds to TNF-α receptor-2 which activates in sequence JAK and STAT-3, conferring cardioprotection via the SAFE pathway [13,14]. Although cross-talk may exist between the RISK and SAFE pathways, IPostC can trigger SAFE pathway independent of its ability to activate the classic RISK pathway [13]. APN may activate the SAFE pathway by stimulating endothelial NO production and subsequent TNF-α production in the cardiomyocyte [31,43]. APN can also activate AMPK which may trigger JAK/STAT-3 signaling [31]. On the other hand, AMPK can directly activate eNOS and inhibit iNOS [33,35-37]. The resulting increase in NO bioavailability then confers cardioprotection [47].

Therefore, we hypothesize that APN may become one of the most promising therapies to restore diabetic heart sensitivity to IPostC. Future studies need to be conducted to test this intriguing hypothesis and to explore the mechanism in order to identify new therapeutic targets to elevate diabetic circulating APN by either genetic or pharmacological approaches, which will facilitate the development of novel and optimal therapies to enhance cardioprotection in patients with severe diseases such as diabetes.

Compliance with ethics guidelines

Tingting Wang, Shanglong Yao, Zhengyuan Xia, and Michael G. Irwin declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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