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The source of ROS produced in cardiovascular systems includes NADPH oxidase, xanthine oxidase, uncoupling of endothelial NO synthase (eNOS) as well as mitochondria. In particular, NADPH oxidase has been considered as a predominant source of ROS in the pathogenesis of hypertension, atherosclerosis, cardiac hypertrophy, and heart failure. Recent data suggest that Ang II, a potent hypertensive hormone which is known to activate NADPH oxidase, induces mitochondrial dysfunction, which in turn promotes excess amount of ROS such as O2•−, H2O2, and peroxynitrite from mitochondria1. This contributes to endothelial dysfunction by reducing NO bioavailability and activating apoptotic signaling, thereby progressing cardiovascular disease, neurodegenerative disease, and aging. Role of mitochondrial ROS is demonstrated by previous reports that transgenic mice overexpressing catalase targeted to the mitochondria exhibit extended lifespan2. Mice overexpressing peroxiredoxin-3, the mitochondria-specific peroxidase linked to thioredoxin-2 (Trx2), show improved survival after myocardial infarction (MI)3. Furthermore, Ang II-converting enzyme inhibitors and Ang II type I receptor blockers prevent age-related mitochondrial dysfunction, hypertension-induced renal mitochondrial dysfunction, and cardiac mitochondrial dysfunction in thesetting of acute ischemia1. However, the role of mitochondria-derived ROS and its relationship with NADPH oxidase-derived ROS in Ang II-induced hypertension remain unclear.
One of the major antioxidant defence systems against mitochondrial ROS (in particular, H2O2) is thiol-reducing systems including thioredoxin (Trx), glutaredoxin, and glutathione system. The Trx system (Trx, Trx reductase, and NADPH) reduces oxidized cysteine groups on protein through an interaction with the redox-active center of Trx (Cys-Gly-Pro-Cys) to form a disulfide bond, which in turn can be reduced by Trx reductase and NADPH. In mammals there are at least three different thioredoxins: Trx1 is present in the cytosol but can also translocate to the nucleus; Trx2 has a consensus signal for translocation to the mitochondria; and SP-Trx is found in spermatozoa. Mitochondrial Trx systems (Trx2, TrxR2, and Prx3) are critical in protecting cells from mitochondria-dependent ROS and apoptosis 4. Little is known about the functional roles of Trx2 in hypertension.
In this issue of Hypertension, using transgenic mice overexpressing Trx2 (hTrx2-Tg), Widdler et al. provide the novel evidence that mitochondrial antioxidant Trx2 plays a critical role in regulating endothelial function and systolic blood pressure in Ang II-induced hypertension5. Overexpression of Trx2 decreases “total“ as well as “mitochondrial“ ROS in aortas from mice infused with Ang II, suggesting that mitochondrial ROS play a critical role in regulating Ang II-induced hypertension. A cross-talk between NADPH oxidase- and mitochondria-derived ROS appears to exist in Ang II-induced mitochondrial dysfunction, ROS production, and preconditioning and nitroglycerin-triggered vascular dysfunction6–8. Ang II activates NADPH oxidase, thereby elevating cytosolic ROS (in particular, O2•−), which triggers mitochondrial ROS elevataion. This mechanism seems to be mediated through either activation of the mitochondrial ATP-sensitive potassium channel (mitoKATP) or mitochondrial dysfunction induced by peroxynitrite produced by the reaction of O2•− with NO. This mitochondrial ROS further increases ROS by inducing mitochondrial permeability transition (ROS triggered ROS formation)9. In this study, uncoupling eNOS may not be a source for Ang II-induced O2•− production, since aortic tetrahydrobiopterin levels as well as eNOS dimer to monomer ratio are not changed after chronic Ang II infusion. Widdler et al. have found that chronic Ang II-infusion increases expression of the NADPH oxidase subunits Nox2, p22phox, p47phox and Rac-1 in wild-type mice, which is attenuated in mice overexpressing Trx25. These results suggest that mitochondrial ROS increases expression of NADPH oxidase components. Given that the NADPH oxidase can be stimulated by H2O2 and lipid peroxides10, the mitochondrial ROS, including H2O2, then might stimulate NADPH oxidase activity and expression in a feed-forward fashion. Thus, decrease in NADPH oxidase expression and “total” ROS production in Ang II-infused hTrx2-Tg mice might be caused by inhibition of cross-talk between mitochondrial- and NADPH oxidase-derived ROS (Figure).
The hTrx2-Tg mice improve endothelial dysfunction induced by Ang II infusion5, suggesting that mitochondrial ROS inhibit EC function, as reported previously 11. This protective effect of Trx2 is not due to increase in vascular eNOS levels, because chronic Ang II infusion did not alter vascular eNOS levels in both wild type and hTrx2-Tg mice. Since mitochondrial ROS may stimulate NADPH oxidase, overexpression of Trx2 may block ROS production derived from both mitochondia and NADPH oxidase, thereby efficiently preserving NO bioavailability. The hTrx2-Tg mice also prevent vasoconstriction induced by chronic Ang II infusion, indicating that mitochondrial ROS contribute to Ang II-mediated vasoconstriction. Zhang et al. reported that transgenic mice overexpressing “endothelial specific” Trx2 (EC-hTrx2-Tg) without Ang II infusion promote endothelium-dependent vasorelaxation, and reduce vasoconstriction, superoxide production, and systolic blood pressure.11 However, hTrx2-Tg mice have no effect on these basal responses. This discrepancy may be due to the possibility that Trx2 expression level in ECs is much higher in EC-hTrx2-Tg mice than hTrx2-Tg mice.
Widdler et al. also show that overexpression of Trx2 inhibits cardiac hypertrophy as well as cardiac superoxide levels caused by chronic Ang II infusion5. Mitocohdria dysfunction seems to contribute to cardiac hypertrophy in heart failure as well as ischemia/reperfusion injury. Independent of its antioxidant properties, Trx2 has antiapoptic activity through inhibition of apoptosis signal-regulated kinase 1 (ASK-1) 12. Given that ASK1 is involved in Ang II-induced cardiac hypertrophy and remodeling, it is tempting to speculate that anti-hypertrophic effect of overexpression of Trx2 may be mediated through ASK1.
The data presented by Widder et al. strongly support a critical role of Trx2, as a regulator of mitochondrial ROS, in Ang II-induced hypertension and cardiac hypertrophy (Figure). Moreover, their finding underscores the importance of targeting antioxidants to mitochondria as a new therapeutic strategy to restore vascular function and reduce pathophysiology of hypertension. This may explain the failure of antioxidants as therapeutic agents in a series of clinical trials and emphasizes the relevance of manipulation of ROS at the subcellular level.
There are many unanswered questions. What is the role of endogenous Trx2 in vascular function and hypertension? Since Trx2−/− mice are embryonic lethal, study using Trx2+/− mice will provide new information regarding the functional significance of Trx2 in Ang II-induced hypertension and other cardiovascular diseases. Can overexpression of other mitochondrial thiol reducing systems such as glutathione peroxidase mimic the effect of Trx2? Can overexpression of Trx2 affect other models of hypertension such as DOCA salt hypertension? Addressing these questions will be essential to understand the mechanism of oxidative stress-dependent cardiovascular diseases and aging in which mitochondrial ROS play an essential role.
I would like to thank Dr. Masuko Ushio-Fukai for critical review of the manuscript and helpful comments.
Sources of Funding
This work was supported by 5R01HL070187-08.