Is angiotensin II type 2 receptor a new therapeutic target for cardiovascular disease?

In a previous issue of Experimental Physiology, we demonstrated that overexpression of the angiotensin II type 2 receptor (AT2R) protects cardiac function from cardiac dysfunction induced by myocardial infarction (MI; Qi et al. 2012). Our study was proposed based on previous reports, in which MI increased cardiac AT2R levels (Nio et al. 1995), and stimulation of the AT2R, using a new selective non-peptide AT2R agonist, compound 21 (C21), significantly improved heart function following MI (Kaschina et al. 2008). Using a gene therapy approach, we extended these findings further by demonstrating that moderate overexpression of cardiac AT2R rescues cardiac function, restores the balance between the vasoprotective [angiotensin-converting enzyme 2 (ACE2)–angiotensin-(1–7)–Mas receptor] and vasodeleterious [angiotensin-converting enzyme (ACE)–angiotensin II–angiotensin II type 1 receptor (AT1R)] axes of the renin–angiotensin system (RAS), and decreases collagen expression and infarct size, thus providing further evidence to support the therapeutic potential of AT2R. Additionally, a recent study further elucidated the possible cardioprotective mechanisms of stimulating the AT2R in a MI model (Lauer et al. 2014). Collectively, these reports lead to the following two conclusions. Angiotensin II (Ang II) is a critical hormone of the RAS and exerts important functions in both physiological and pathological conditions. Angiotensin II binds to AT1R and AT2R. The binding of Ang II to the AT2R exerts an opposing effect when compared with the actions mediated by stimulation of the AT1R, and it is generally thought that the AT2R is expressed at lower density than AT1R in adult tissues. However, AT2R has been found to be upregulated in pathophysiological conditions, such as ischaemic injury (Nio et al. 1995). Upregulation of AT2R following injury may occur as a compensatory mechanism to reduce injury and/or repair tissues. However, it is speculated that the endogenous upregulation of AT2R in pathological conditions may not be adequate to exert significant and sustained beneficial effects. It is possible that the upregulation of AT2R may be transient and thus not able to restore normal function. Moreover, AT2R has been thought possibly to mediate some of the protective effects attributed to AT1R antagonists. Blocking AT1R is associated with an increase in unbound Ang II, which can then stimulate AT2R and trigger a molecular cascade to prevent damage to the injured tissue. Thus, overexpression of AT2R using gene therapy techniques or pharmacological stimulation of AT2R, via a receptor agonist, can be used to study the beneficial role of AT2R in cardiovascular disease conditions. Therapeutic effects of overexpression of AT2R for ischaemic heart disease are similar to direct stimulation of AT2R via C21. Kaschina et al. (2008) provided the first pharmacological evidence that stimulation of AT2R with C21 conferred beneficial effects on heart function in MI rats. However, their initial study was carried out for only 1 week following the initial cardiac insult. Recently, this same group demonstrated that continuous stimulation of AT2R by C21 also provides cardioprotection against ischaemic injury in the late stage of MI, 6 weeks after the acute event (Lauer et al. 2014). It has been suggested that there is an underlying connection and interactive regulation between the AT2R and the vasoprotective axis of the RAS. Angiotensin II type 2 receptor expression has previously been confirmed to be correlated directly with angiotensin-(1–7)-forming activity in the ventricles of pulmonary hypertensive patients. The level of AT1R is increased in the myocardium following MI (Nio et al. 1995; Qi et al. 2012), and ACE is upregulated (Qi et al. 2012). Cardiac-selective overexpression AT2R attenuates these changes (Qi et al. 2012). Although overexpression of AT2R did not change Mas receptor levels, it significantly increased the Mas receptor/AT1R ratio and prevented the suggested decrease in the ACE2/ACE ratio observed in the animals with MI (Qi et al. 2012). These findings suggest that overexpression or stimulation of AT2R appears to restore the balance between the vasodeleterious (ACE–Ang II–AT1R) and the vasoprotective (ACE2–angiotensin-(1–7)–Mas receptor) axes of the RAS. Furthermore, several investigators have observed antifibrotic and anti-inflammatory actions of the AT2R. Previous studies have shown that AT1R overactivity causes fibrosis by modulating matrix metalloproteinases and promotes peripheral vascular and tissue inflammation. Angiotensin II type 2 receptor antagonist inhibits collagen degradation by increasing the activity of matrix metalloproteinases 2 and 9 and decreasing the level of tissue inhibitor of metalloproteinases. In agreement with these findings, Lauer et al. (2014) demonstrated that C21 treatment may have provided the beneficial cardiac effects in the MI model by upregulating tissue inhibitor of matrix metalloproteinase 1 and downregulating matrix metalloproteinases 2 and 9 and transforming growth factor to reduce collagen content and inflammation in the peri-infarct myocardium. Our group has also found that overexpression of AT2R attenuates the MI-induced upregulation of collagen I (Qi et al. 2012). Collectively, these studies demonstrate that the level of cardiac fibrosis is significantly reduced with stimulation or overexpression of the AT2R. Recently, the use of this selective non-peptide agonist of AT2R was also shown to provide cerebroprotection in a rodent stroke model, and this cerebroprotective action was attributed to an anti-inflammatory effect (Joseph et al. 2014), consistent with findings in the MI model. In summary, the RAS is a complex system, with more pathways continually being discovered as well as more physiological actions attributed the RAS. The actions of the RAS are much more diverse and comprehensive than the pure homeostatic regulation of blood pressure and salt and water balance usually ascribed to the RAS. Stimulation of the AT2R may indeed offset and/or reverse many of the pathological actions mediated via stimulation of the AT1R. Overexpression or direct stimulation of the AT2R may account for preserved heart function and attenuation of disease-associated cardiopathophysiology by restoring the balance of the RAS axes, anti-inflammatory and antifibrotic effects. Therefore, drugs that can be used to stimulate the AT2R selectively could serve as potential therapeutic agents to treat cardiovascular disease. Readers are invited to give their opinion on this article. To submit a comment, go to: http://ep.physoc.org/letters/submit/expphysiol;99/7/933.