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Cardiovascular Research 2007 76(2):204-212; doi:10.1016/j.cardiores.2007.07.014
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Copyright © 2007, European Society of Cardiology

Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation

Guo-Xing Zhanga,*, Xiao-Mei Lua,b, Shoji Kimuraa and Akira Nishiyamaa

aDepartment of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan
bDepartment of Pathophysiology, College of Basic Medical Science, China Medical University, ShenYang, 110001, China

*Corresponding author. Department of Pharmacology, Medical Faculty, Kagawa University, 1750-1 Miki-cho, Kagawa 761-0793, Japan. Tel.: +81 87 891 2125; fax: +81 87 891 2126. deep_red_maple{at}yahoo.com.cn

Received 9 April 2007; revised 12 July 2007; accepted 23 July 2007


   Abstract
Top
 Abstract
1. Introduction
 2. ROS generation in...
 3. Role of membrane-bound...
 4. Role of mitochondria...
 5. Relationship between NAD(P)H...
 6. Role of mitochondria...
 7. Future direction
 References
 
Peptide hormone Angiotensin II (Ang II) activates NAD(P)H oxidase, via AT1 receptors leading to increased generation of reactive oxygen species (ROS), such as the superoxide anion (O2–). As an important intracellular second messenger, ROS can activate many downstream signaling molecules, including mitogen-activated protein kinases (MAPK), protein tyrosine phosphatases, protein tyrosine kinases, and transcriptional factors. Activation of these signaling cascades is highly related to risk for cardiovascular diseases. Accumulating evidence reveals that membrane-bound NAD(P)H oxidase is the main source responsible for Ang II-induced ROS generation. However, recent novel findings suggest that Ang II stimulation induces opening of mitochondrial KATP channels, depolarizes mitochondrial potential ({Delta}{psi}M), and further amplifies ROS generation from mitochondria, resulting in redox-sensitive activation of MAPK. In this review, we discuss the possible mechanisms of Ang II-induced cardiac pharmacological preconditioning (PC), and focus on the role of mitochondrial KATP channels, mitochondrial ROS production, and MAPK activation in response to Ang II stimulation.

KEYWORDS Angiotensin II (Ang II); Mitochondrial KATP channel; Mitogen-activated protein kinase (MAPK); Reactive oxygen species (ROS); Preconditioning (PC)


   1. Introduction
Top
 Abstract
 1. Introduction
2. ROS generation in...
 3. Role of membrane-bound...
 4. Role of mitochondria...
 5. Relationship between NAD(P)H...
 6. Role of mitochondria...
 7. Future direction
 References
 
Extensive investigation over the last few decades has demonstrated that angiotensin II (Ang II) affects cell growth, differentiation and apoptosis, induction of pro-inflammatory cytokines, and fibrogenesis, in addition to its classical hemodynamic function of regulating of blood pressure and fluid and electrolyte homeostasis [1–4]. The cellular mechanisms and signaling pathways by which Ang II induces tissue damage are currently the subject of intensive investigation. One of the most prominent concepts to emerge in relation to Ang II mechanisms is induction of reactive oxygen species (ROS) and activation of redox-dependent signaling cascades, which are critical processes underlying various cardiovascular diseases, such as hypertension, diabetes, atherosclerosis and myocardial infarction [5–7]. Further, it has been demonstrated that non-phagocytic membrane-bound NAD(P)H oxidase is essential for Ang II-induced ROS generation in the cardiovascular system [8,9].

Although most investigations of Ang II mechanisms to date have focused on NAD(P)H oxidase as a key mediator, other potentially important mechanisms have begun to emerge. Increasing evidence suggest that the mitochondrial electron transport chain (METC) is also regulated by ROS [10–12]. Recently, it has been demonstrated that mitochondrial KATP channels also played an important role in response to Ang II-induced ROS generation and MAPK activation in vascular smooth muscle cells (VSMC) [13], and in Ang II-induced pharmacological preconditioning (PC) effects in cardiac ischemia–reperfusion [14,38,39].

In this review, we will introduce recent progress in the study of the mechanisms by which Ang II induces ROS generation in cardiovascular cells, and focus on the role of NAD(P)H oxidase and mitochondrial KATP channels in Ang II-induced ROS generation and MAPK activation. A better understanding of these key events will provide further insight into the processes underlying cardiovascular diseases, and may identify potential novel therapeutic targets for their prevention and management.


   2. ROS generation in response to Ang II stimulation
Top
 Abstract
 1. Introduction
 2. ROS generation in...
3. Role of membrane-bound...
 4. Role of mitochondria...
 5. Relationship between NAD(P)H...
 6. Role of mitochondria...
 7. Future direction
 References
 
As early as 1990, Wilson observed that superoxide dismutase (SOD) and dimethyl sulfoxide (DMSO) inhibited vascular hyper-permeability and cellular damage during acute Ang II-induced hypertension [15]. Later, it was demonstrated that hypertension caused by chronically elevated Ang II is mediated in part by superoxide (O2–), suggesting that increased vascular O2– contributes to vascular disease in high rennin-Ang II states [16–18]. Ang II-induced cardiac hypertrophy was also shown to be by ROS, which can be reduced by antioxidant treatment [19,20]. Consistent with the in vivo observations, in vitro data also supported the idea that Ang II stimulation increases O2– and H2O2 generation, and has been demonstrated in cultured VSMCs [21–23], endothelial cells (EC) [24,25], fibroblasts [26], cardiac myocytes [141] and fibroblasts [27,28]. Furthermore, Ang II-induced O2– inactivates nitric oxide (NO) and promotes the formation of peroxynitrite, leading to endothelial dysfunction [135,136]. Ang II exerts pharmacological PC effects against cardiac ischemic reperfusion injury [14,33–35]. Based on current knowledge, both O2– and nitric oxide (NO) are required in signal transduction of cardiac PC [36,37,137]. Although there is no direct evidence demonstrating that Ang II-induced pharmacological PC involves NO, several independent research groups have shown that ROS mediates Ang II-induced pharmacological PC [14,38,39]. All of these data suggest that Ang II stimulation increases cardiovascular ROS generation, which is involved in cellular signal transduction and tissue function, resulting in organ injury and dysfunction or recovery.


   3. Role of membrane-bound NAD(P)H oxidase in Ang II-induced ROS generation
Top
 Abstract
 1. Introduction
 2. ROS generation in...
 3. Role of membrane-bound...
4. Role of mitochondria...
 5. Relationship between NAD(P)H...
 6. Role of mitochondria...
 7. Future direction
 References
 
Ang II elicits its actions via AT1 and AT2 receptors. Most known functional effects of Ang II are mediated via AT1 receptors, which couple to multiple, interacting signal transduction cascades, leading to diverse biological actions. An interesting finding in the field of cardiovascular Ang II signaling is that AT1 receptor activation stimulates non-phagocytic NAD(P)H oxidase and generation of O2– in various cardiovascular cell types. The main features of neutrophil NAD(P)H oxidase have been well documented and reviewed previously [40,41]. In parallel with the progress in neutrophil NAD(P)H oxidase, a series of observations discovered the existence of non-phagocytic NAD(P)H oxidase. It has now been identified: seven NOX isoforms, two organizer subuits (p47phox, NOXO1), two activator subunits (p67phox, NOXA1), and two DUOX-specific maturation factors (DUOXA1 and DUOXA2) [46]. Additional components of the enzyme include p22phox, p40phox and the small G proteins Rac and Rap1A. Recently, it has become clear that cardiovascular cells also express NAD(P)H oxidase with a specific pattern of Nox. Nox1, Nox2, Nox4, and Nox5 express in arteries [29] in VSMCs, the message for Nox1 and Nox4 are abundantly expressed [29,42,43], endothelial cells mostly express Nox4 [30,44,45], although message of Nox1 [31,32], Nox2 [32,107] and Nox5 [108] have been described. While in cardiomyocytes, Nox function can be divided in a developmental function [109] and a function in adult cardiomyocytes. During development, Nox4 plays a pivotal role in inducing cardiac differentiation [133]. In adult heart, Nox2 is the predominant isoform, and transduces down-stream signaling cascades [142,143]. Fibroblasts widely express both Nox2 and Nox4 [47–49]. Unlike the leukocyte, whose NAD(P)H oxidase is inactive in the absence of stimulation [40,41], in cardiovascular cells it was demonstrated that part of the oxidase is pre-assembled [50–52]. The role of NAD(P)H oxidase in cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial ischemic reperfusion injury, cardiac hypertrophy, fibrosis, and heart failure was well documented [45,46]. NAD(P)H oxidase activity is regulated by both post-translational modification of its regulatory subunits and transcriptional pathway [45,53]. Evidence from VSMCs demonstrated that Ang II induces NAD(P)H oxidase activation and stimulates ROS generation [21,23]. Data from other cardiovascular cell types including cardiac myocytes [54], cardiac muscle cell line [55], and endothelial cells [46], also supported that concept that Ang II stimulation activates NAD(P)H oxidase. Upon stimulation with Ang II, cytosolic subunits can translocate to the membrane fraction to form an active NAD(P)H oxidase [56]. Translocation and phosphorylation of the NAD(P)H oxidase subunits may contribute to a rapid increase in ROS production [57]. Solid evidence has shown up-regulation of mRNA and/or protein of all major oxidase subunits, including catalytic Nox1, Nox2 and Nox4, and cytosolic subunits p67phox, p47phox, and p40phox, upon stimulation with Ang II [56,59,60]. Each component of NAD(P)H plays an essential role in Ang II-induced ROS production in VSMCs [56] and aortic tissue [58,61,62]. In cardiac tissue, Bendall et al. found that Nox2 plays an essential role in short-term Ang II-induced cardiac hypertrophy [63]. In isolated cardiomyocytes, the small GTP-binding protein Rac was reported to be involved in Ang II-induced cell hypertrophy [64]. NAD(P)H oxidase inhibitors can significantly supress ROS generation in response to Ang II both in vitro and in vivo [14,21,62], and also prevent Ang II from inducing an increase in NAD(P)H oxidase acitivity and up-regulation of mRNA and proteins of NAD(P)H oxidase subunits.


   4. Role of mitochondria in response to Ang II stimulation
Top
 Abstract
 1. Introduction
 2. ROS generation in...
 3. Role of membrane-bound...
 4. Role of mitochondria...
5. Relationship between NAD(P)H...
 6. Role of mitochondria...
 7. Future direction
 References
 
It is well known that the mitochondria are the major source of ROS in cells. This is indeed the case in tissues in which mitochondria represent a substantial proportion of the cell mass, such as in the heart or brain, as well as in other tissues less abundant in mitochondria in some special conditions. Previous studies on mitochondrial ROS have demonstrated that both complex I and complex III of the mitochondrial electron transport chain (METC) are involved in the univalent reduction of O2 to O2– [65,66]. This subject has been widely reviewed by others [67,68]. Since the identification of KATP channels, which are also located in the inner mitochondrial membrane and termed mitochondrial KATP channels (mitoKATP), the molecular composition, biophysical properties and integration with cellular metabolic pathways have been widely investigated [69,70,144]. More recently, the functional significance of its membrane metabolic sensors and effectors of cytoprotection under various stress conditions has been further established, and its role in health and disease has been reviewed [71]. Almost all the evidence indicates the involvement of KATP channels in myocardial PC [72,73]. Initially, evidence suggested that the surface or sarcolemmal KATP channels trigger or mediate the cardioprotective effects of PC; however, more recent findings have suggested a major role for mitoKATP channels in cardiac PC [74,75]. It was also demonstrated that not only in PC but also in post-conditioning, mitoKATP channels protected against cardiac injury through a redox-sensitive mechanism [76–78]. Collectively, these observations suggest a signal transduction pathway in which opening of mitoKATP channels results in the mitochondrial production of ROS which protects the heart from ischemic–reperfusion injury. Besides the evidence in cardiac PC and post-conditioning, in VSMCs it has been demonstrated that opening of mitoKATP channels by diazoxide or pinacidil (both potent mitoKATP channel openers) can induce increased ROS generation via the METC [13,79]. These observations further support the concept that opening of mitoKATP channels induces increased ROS generation in the METC, which might be involved in down-stream signaling transduction. Although the activities of both mitoKATP channels [80] and sarcolemmal KATP channels [81] can be regulated by protein kinase C, cardiac PC and post-conditioning are mainly triggered by mitoKATP channels [72,73,77,82]. Since protein kinase C could be activated through activation of AT1 receptors by Ang II, prior to ischemia, and limits myocardial infarction [34,83], it may be speculated that Ang II-induced activation of protein kinase C may involve mitoKATP channel-opening, triggering the pharmacological PC. Although protein kinase C can regulate the acitivities of both mitoKATP channels [80] and sarcolemmnal KATP channels [81,143], cardiac PC and post-conditioning mainly involve mitoKATP channels [72,73,77,82]. Since Ang II administration prior to ischemia activates protein kinase C [34,83], it may be speculated that pharmacological PC of Ang II is triggered by mitoKATP channel-opening. The functional effects of opening mitoKATP channels are still controversial, and the relationship between protein kinase C and channels need to be further elucidated.


   5. Relationship between NAD(P)H oxidase and mitochondria in Ang II-induced ROS generation
Top
 Abstract
 1. Introduction
 2. ROS generation in...
 3. Role of membrane-bound...
 4. Role of mitochondria...
 5. Relationship between NAD(P)H...
6. Role of mitochondria...
 7. Future direction
 References
 
It is traditionally recognized that membrane-bound NAD(P)H oxidase is essential and the main source for Ang II-induced ROS production in blood vessels. Meanwhile, Ang II exerts pharmacological PC effects through mitochondrial generated ROS. It has become necessary to clarify the paradigm for the source of Ang II-induced ROS generation. Interestingly, several studies have shown that ROS generated by NAD(P)H oxidase can serve to promote further ROS generation by other sources. For example,NAD(P)H oxidase-derived O2– may oxidize and degrade tetrahydyrobiopterin (BH4), thereby resulting in NOS uncoupling to generate O2– in ApoE-deficient mice and experimental hypertension [84,85]. Similarly, H2O2 stimulated conversion of dehydrogenase to xanthine oxidase leading to further production of ROS [86]. The question is whether NAD(P)H oxidase-derived ROS could enhance ROS production from mitochondria in response to Ang II stimulation? Several studies support this hypothesis. Firstly, addition of an O2– generation system results in marked activation of reconstituted myocardial mitoKATP channels in vitro [11]. This indicates that O2– itself activates the mitoKATP channels, emphasizing that exogenous ROS can affect mitochondrial function through the mediation of mitoKATP channels. Secondly, there is the evidence relating to the mitochondrial permeability transition (MPT), which is large voltage-gated channel that opens in response to calcium overload and oxidative damage of constituent proteins [12,87,88], and which played an important role in cardiac PC and postconditioning [89–92]. Zorov et al recently devised a new model enabling incremental ROS accumulation in individual mitochondria in isolated cardiac myocytes via photoactivation of tetramethylrhodamine derivatives (TMRM, tetramethylrhodamine, methyl, and ethyl ester), which also served to report the mitochondrial transmembrane potential ({Delta}{psi}M). Photoexcitation of TMRM caused the production of ROS which triggered the abrupt loss of mitochondrial {Delta}{psi}M [10]. They ascribed this phenomenon to MPT induction because of the following evidence (1) bongkrekic acid (inhibitor of MPT induction) prevented MPT induction and (2) mitochondria become permeable to calcein (~ 620Da) concurrent with depolarization. They also observed that MPT induction caused by triggering ROS coincided with a burst of mitochondrial ROS generation, as measured by dichlorofluorescein fluorescence, and have termed this mechanism as mitochondrial "ROS-induced ROS release" (RIRR). The mechanisms of the ROS burst accompanying MPT remain unclear, although under ordinary conditions mitochondrial complexes I and III are believed to be the major sources of ROS [65, 66]. Zorov et al. has also shown that the diversion of electrons from the respiratory chain provides the source of the ROS burst. Recently, it was described that two mechanisms are involved in RIRR: one is increased ROS which leads to mitochondrial depolarization via activation of MPT, yielding a short-lived burst of ROS originating from METC, the other is MPT-independent, but is regulated by the mitochondrial benzodiazepine receptor, increased ROS reaching a threshold level that triggers opening of the requisite mitochondrial membrane anion channels, resulting in a brief increase in METC-derived ROS [93, 94]. Recently, we have observed that Ang II stimulation depolarizes {Delta}{psi}M within short time periods (~ 5min) following the increase in O2– generation in VSMCs [13], which we postulate was due to the NAD(P)H oxidase-derived ROS inducing MPTP formation, and resulting in respiratory burst. Although the role of mitoKATP channels in the vascular tissues is still controversial, it has been postulated that O2– inhibits the opening of mitoKATP channels, and H2O2 activates the mitoKATP channels [95]. By investigating the role of ROS in Ang II-induced pharmacological PC in cardiac ischemia–reperfusion, we have shown that pretreatment with the NAD(P)H oxidase inhibitor apocynin suppresses the increase in cardiac lipid peroxidation and PC effects of Ang II [14]. This points to a crucial role for NAD(P)H oxidase in cardiac Ang II signaling pathways. According our observation, the mitoKATP channels is the downstream of the NAD(P)H oxidase, since the specific inhibitor of mitoKATP channels, 5-HD, reverses the Ang II-induced preconditioning effects, similarly to apocynin, without affecting NAD(P)H oxidase complex formation and its activity [14]. These data indicate that pharmacological PC effects by Ang II are mainly mediated by opening of mitoKATP channels. According to the mechanisms of RIRR, NAD(P)H oxidase originated ROS may serve as a trigger to induce opening of mitoKATP channels leading to the mitochondrial ROS burst, which in turn mediates the PC effects by Ang II. On a note of caution, diphenyleneiodonium (DPI) was traditionally administrated as an NAD(P)H oxidase inhibitor in response to Ang II stimulation; however, it has also been demonstrated that DPI potently inhibits mitochondrial ROS production [96]. It should be noted that whether this RIRR mechanism can be extrapolated to other cell lines remains to be established.


   6. Role of mitochondria in Ang-induced MAPK activation
Top
 Abstract
 1. Introduction
 2. ROS generation in...
 3. Role of membrane-bound...
 4. Role of mitochondria...
 5. Relationship between NAD(P)H...
 6. Role of mitochondria...
7. Future direction
 References
 
MAPK constitutes a superfamily of serine/threonine protein kinases involved in the regulation of a number of intracellular pathways. Mammalian MAPKs are grouped into six major subfamilies: (1) ERK-1/ERK-2; (2) JNK/stress-activated protein kinases; (3) p38; (4) ERK-6, p38-like MAPK; (5) ERK-3; and (6) ERK-5 (also called big MAP kinase 1) [97,98]. MAPK-dependent signaling pathways are associated with cell growth and apoptosis, cell differentiation and transformation, and vasocontraction [99,100]. The ERKs are activated in response to growth and differentiation factors, whereas c-jun N-terminal kinases (JNKs) and p38 are usually activated in response to inflammatory cytokines and cellular stress [97,101,102]. In VSMCs, Ang II rapidly activates phosphorylation of the MAPK family, ERK1/2, p38 and JNK [103]. In cardiomyocytes, as well as cardiac fibroblasts, Ang II rapidly cause tyrosine phosphorylation and activate ERK1/2 MAPK [104]. JNK and p38 MAPKs are also activated by Ang II in cultured cardiomyocytes [105,106]. In vivo, we and other researchers have shown that acute Ang II administration stimulates cardiovascular and renal MAPK activation [18,110]. The MAPK pathways comprise a three-component protein kinase cascade consisting of a serine/threonine protein kinase which phosphorylates and activates a dual-specificity protein kinase, which in turn phosphorylates and activates another protein kinase [97]. Among the MAPK family, Ang II stimulates the ERK-dependent pathway via AT1 receptors, and is associated with increased expression of the early response genes c-fos, c-myc, and c-jun, DNA synthesis, cell growth and differentiation, and cytoskeletal organization in VSMCs [111,112]; Ang II-stimulated activation of JNK is supposed to regulate cell growth by promoting apoptosis or by inhibiting growth [102,113]. The exact functional effects of Ang II-induced activation of ERKs and JNK are still not well defined, but regulation of cell growth may be important as Ang II-activated ERKs and JNK have opposite growth effects, with ERKs being facilitative and JNK inhibitory. However, it has been reported that JNK mediates the proliferative effects of Ang II in cultured human MCs [114]. These signaling-process-associated cellular functions are potentially important in enhanced vascular contractility, hyperplasia, and/or hypertrophy in hypertension [115]. Ang II-activated p38 MAPK plays an important role in inflammatory responses and apoptosis, and is involved in inhibition of cell growth cell contraction [102,109,115,116]. The p38 MAPK pathway has been implicated in cardiac ischemia, ischemia–reperfusion injury, cardiac hypertrophy, progression of atherosclerosis, and arterial remodeling in hypertension. In 1996, two independent groups demonstrated activation of MAPK, particularly the JNK and p38 pathways, in the rat heart subjected to ischemia–reperfusion [117,118]. Furthermore, it has been reported that ischemic PC induces ERK1/2, p38 and JNK MAPK activation [119,120]; however, the exact role of MAPK activation in ischemic PC is still unclear. Through administration of the p38 antagonist SB-203580, Mocanu et al. have demonstrated that activation of p38 MAPK during lethal ischemia, but not during ischemic PC, is essential for protection [119]. Fryer et al. has observed that SB-203580 inhibits JNK MAPK activation during early reperfusion, accompanied by elimination of ischemic PC [120]. MEK-ERK1/2 inhibitor PD98059 abolishes the effects of ischemic PC [121]. These observations suggest the involvement of MAPK in ischemic preconditioning. On the other hand, Clerk et al. [122] have explored the redox regulation of these events by comparing the influence of H2O2 to that of ischemia and ischemia–reperfusion on JNK and p38 activation. H2O2 appears to mimic the effect of ischemia–reperfusion, and free-radical-trapping agents inhibit the activation of MAPK by ischemia–reperfusion, demonstrating the role of ROS in the process and introducing the paradigm that antioxidants might play a regulatory role in the activation of MAPK during ischemia–reperfusion. Based on extensive observation of ischemic PC, it is now widely accepted that ROS generated in the mitochondrial respiratory chain act as a trigger. ROS mediate signal transduction in the early phase of ischemic PC through the posttranslational modification of redox-sensitive proteins. Apart from binding to the AT1 receptor, Ang II activates receptor tyrosine kinases through transactivation of growth factor receptors such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) [123,124]. This transactivation allows the EGFR to act as a scaffold for other signaling proteins, ultimately leading to activation of MAPK. Existing evidence suggests that this transactivation of receptor tyrosine kinases may also be involved in Src and mediated by ROS [125,126]. Src protein kinase can acts as the trigger to modulate signal transduction in cardiac PC [127,128]. We and other researchers have shown that Ang II-induced MAPK activation is redox-sensitive both in vitro and in vivo [23,38,129,130]. There is now a body of evidence which demonstrates that MAPKs, including ERK1/2, p38, and JNK, are sensitive to mitochondria-derived ROS in several kinds of models. In cardiomyocytes, Kulisa et al. reported that hypoxia-induced p38 activation is mediated by METC-derived ROS [131]. Schafer et al. demonstrated that mitochondrial originated ROS was the upstream of ERK2 activation of EC hypoxia [132]. We recently have revealed that Ang II-induced MAPK activation in cardiovascular tissues [130] and rat VSMCs [13] is sensitive to the radical scavenger tempol, confirming that activation of MAPK is redox-sensitive. This study also demonstrated that activation of stress-inducible p38 and JNK MAPK are prevented by 5-HD in rat VSMCs [13], indicating the important role of miotKATP channels in the activation of p38 and JNK MAPK in response to Ang II stimulation. Furthermore, we also demonstrated that the pharmacological PC effects of Ang II are eliminated by both NAD(P)H oxidase, radical scavengers, and miotKATP channel blockers [14]. Although our data have not shown direct evidence to support an involvement of mitochondrial-derived ROS in Ang II induced MAPK, Ang II-induced ROS generation may be according to the RIRR mechanism, which is NAD(P)H oxidase derived ROS stimulates the mitochondrial derived ROS. Taken together with above mentioned observations, it is plausible to assume that mitochondria-derived ROS are involved in p38 and JNK MAPK activation, especially in cardiac PC and postconditioning models. However, according to our data in VSMCs, the Raf/MEK/ERK pathway is not so sensitive to 5-HD, indicating another pathway independent of mitochondrial originated ROS might be involved in the Ang II-induced Raf/MEK/ERK pathway [11]. Since it was already demonstrated that the MEK-ERK1/1 pathway was also involved in Ang II induced cardiac PC [134], this discrepancy may be due to the different model and different administration methods of respective blockers. It may also be due to ERK activation involved other ROS insensitive pathway. Although Ang II could induce NO synthase activation [138,139], and NO is involved in cardiac PC [137] and postconditioning [140], there is still no supporting evidence that Ang II-induced pharmacological PC is mediated by activation of NO synthase. Further studies are needed to elucidate the possible contribution of MAPK to Ang II-induced ischemic preconditioning, especially the MEK-ERK1/2 MAPK pathway. More work is also needed to explore the role of NAD(P) oxidase and NO synthase in cardiac PC response to Ang II. In conclusion, evidence supports a mechanism in which Ang II stimulation activates NAD(P)H oxidase to generate ROS, which activates miotKATP channels to induce a ROS burst in the mitochondria to activate down-stream signaling pathways, such as activation of p38 and JNK MAKP, involved in cell apoptosis, hypertrophy and differentiation (Fig. 1).


Figure 1
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  		Fig. 1 Potential signaling pathway in Angiotensin II (Ang II) stimulation. Ang II binds to Ang II type I receptors (AT1-R), activates protein kinase C (PKC), which activates NADPH oxidase to induce superoxide (O2–) generation. Mitochondrial KATP channels can be activated by O2– to produce more generation of reactive oxygen species (ROS) to induce activation of mitogen-activated protein kinase (MAPK), which mediates Ang II induced cell proliferation and apoptosis, etc. Angiotensin II receptor blocker (ARB), PKC inhibitor (GFX1092303X), NAD(P)H oxidase inhibitor (Apocynin), Mitochondrial KATP channel inhibitor (5-HD), ERK inhibitor (PD98059), JNK inhibitor (SP600125), p38 inhibitor (SB203580).

 

   7. Future direction
Top
 Abstract
 1. Introduction
 2. ROS generation in...
 3. Role of membrane-bound...
 4. Role of mitochondria...
 5. Relationship between NAD(P)H...
 6. Role of mitochondria...
 7. Future direction
References
 
During the past few years, our understanding of the role of NAD(P)H oxidase in response to Ang II stimulation has increased steadily. However, significant work remains to be carried out to elucidate the role of mitochondria in response to Ang II stimulation. It is also necessary to establish the role of ROS and MAPKs in response to Ang II stimulation. Such studies may provide novel insights into the mechanisms of Ang II-dependent diseases such as cancer, atherosclerosis, and hypertension, and provide potential therapeutic targets for promoting myocardial angiogenesis in ischemic heart disease.


   References
Top
 Abstract
 1. Introduction
 2. ROS generation in...
 3. Role of membrane-bound...
 4. Role of mitochondria...
 5. Relationship between NAD(P)H...
 6. Role of mitochondria...
 7. Future direction
 References
 

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