The possible constitutive activity of wild-type angiotensin II type 1 receptor

Wild-type (WT) G-protein coupled receptors (GPCRs), such as the α_1B adrenergic receptor, β₂ adrenergic receptor, 5-HT₁ receptor and angiotensin II (Ang II) type 2 (AT₂) receptor, display constitutive or spontaneous activities in the absence of an agonist.^{1, 2, 3} In addition, several naturally occurring and disease-causing GPCR mutants with increased constitutive activity relative to WT GPCRs have been identified,⁴ although no naturally occurring mutation in the AT₁ receptor can induce constitutive activity. If the Ang II type 1 (AT₁) WT receptor does have constitutive activity, we should be able to use this activity to classify many AT₁ receptor blockers (ARBs). Classifying clinically available ARBs as neutral agonists or inverse agonists should help to block the basal functionality of the AT₁ receptor.

It is unclear whether the constitutive activity of the AT₁ receptor could have a pathophysiological role or whether the blockade of this activity by an inverse agonist would help to prevent the progression of cardiovascular disease (CVD). To address this question, in this issue of Hypertension Research, Hasan et al.,⁵ reported that inverse agonism of the AT₁ receptor attenuates spontaneous proinflammation and enhances the constitutive insulin-sensitizing activity of mature adipocytes. Inflammation and insulin-sensitizing activity contribute to the onset and progression of atherosclerotic CVD. High-dose valsartan reduced both the constitutive and Ang II-induced expression and secretion of interleukin-6 in mature adipocytes. The constitutive activity of the AT₁ receptor is thought to have a critical role in increasing inositol phosphate (IP) production.⁶ Mechanical stress induces the constitutive activity of the AT₁ receptor and activates extracellular signal-regulated kinase, which contributes to cardiac remodeling.⁷ However, losartan did not demonstrate inverse agonist activity toward IP production. The AT₁ receptor transgene in angiotensinogen-knockout mice showed cardiac enlargement, interstitial fibrosis and contractile dysfunction, which suggested that the transgenic myocardial overexpression of the AT₁ WT receptor increases the constitutive activity of the receptor, which leads to cardiac remodeling in the absence of Ang II.⁷ Thus, inverse agonism of the AT₁ receptor may be important in preventing CVD progression. Apart from these reports, Hasan et al.,⁵ were the first to indicate that the AT₁ WT receptor in adipocytes produced constitutive activity in adipocytokines. As obese rats exhibited marked upregulation of the AT₁ receptor mRNA and protein expression,⁸ the pathological condition may be important. The authors proposed that the enhanced expression and secretion of adiponectin in mature adipocytes should also be a beneficial effect of valsartan in obese patients.

There is another important issue regarding the inverse agonism of ARB in mature adipocytes in Hasan’s study.⁵ Although valsartan and olmesartan have been shown to exhibit inverse agonism,^{6, 9} the authors did not analyze other ARBs. ARBs have been shown to demonstrate ‘class’ effects or ‘common’ effects. However, not all ARBs have the same effects, and some beneficial effects conferred by ARBs may be ‘off-target’ effects or ‘molecular’ effects rather than class effects.^{10, 11} We have proposed that the common molecular structures of ARBs might be responsible for their class effects, whereas their slightly different structures may be important for promoting molecule-specific effects.¹⁰ Valsartan exhibits a strong inverse agonistic effect for IP production on AT₁ receptor.⁶ However, valsartan is not an agonist for peroxisome proliferator-activated receptor (PPAR)-γ.¹² Other ARBs, such as telmisartan and irbesartan, have been shown to exhibit agonism for PPAR-γ as an off-target effect.^{13, 14} In addition, irbesartan inhibited monocyte chemoattractant protein-1 production from endothelial cells independent of the AT₁ receptor, and this effect may be mediated by nuclear factor kappa-B (NF-κB) inactivation.¹⁴ The off-target effect of inverse agonism by inhibiting the constitutive activity of the AT₁ receptor by valsartan may also benefit anti-inflammation and enhance insulin-sensitizing activity. As mentioned above, valsartan did not directly stimulate PPAR-γ as an off-target effect. Interestingly, the inverse agonism of valsartan induced NF-κB inactivation and evoked cross-talk between NF-κB and PPAR-γ. PPAR coactivator-1α, which is essential for the transcriptional activity of PPAR-γ, was upregulated by valsartan. Thus, each ARB has critical and beneficial off-target effects. These effects may be caused by differences in the cell signaling mechanisms and in the types of cells.

Hasan’s study has several limitations, which the authors noted.⁵ The doses of Ang II and valsartan were fixed at relatively high levels. It is unclear whether a relatively high concentration of valsartan is clinically relevant. The precise mechanisms underlying the constitutive activity of the AT₁ receptor inducing cell signaling in the NF-κB and PPAR-γ pathways are unclear. Further studies will be needed to clarify these points to ensure that we can clearly recognize the beneficial effects of the inverse agonism of valsartan.

In conclusion, Hasan’s data clearly show that valsartan has beneficial off-target effects.⁵ Although we can expect that other ARBs also have beneficial off-target effects, we must be careful when comparing their results and interpreting their clinical impacts. We should also reconsider whether ARBs have other beneficial off-target effects in addition to their class effects.