Proposed interaction between angiotensinogen and retinoblastoma tumor suppressor protein: Potential molecular origin of hypertension

Abstract

Cardiovascular disorders are still the most common cause for morbidity and mortality in industrialized countries. Within this major group of diseases, hypertension plays a leading role. Similar to other important pathologies such as cancer, the prevalence of hypertension increases with aging (1). Currently, among the principal treatments for hypertension are calcium-channel blockers, β-adrenergic antagonists and substances interfering with the reninangiotensin system such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (1). However, it is also known that the therapy of hypertension needs further improvement since it is not infrequent that polypharmacy by means of several different antihypertensive agents is needed to control certain forms of hypertension and, moreover, other (malignant) variants of hypertension are refractory to antihypertensive drug treatment.As a result, the present investigation has aimed for identifying novel antihypertensive drug targets. In this context, I have focused on the potential pathogenetic role of angiotensinogen, i.e. the precursor protein for the hypertensive peptide angiotensin II, that has previously been described to occur in the intracellular compartment of human astrocytes (2) and of human dopaminergic neurons of the substantia nigra compacta (3). Discovery and hypothesis:In the course of analyzing the amino acid sequence of human angiotensinogen, I have now discovered that it harbors the LXFXE amino acid motif (Figure 1) that has previously been defined as a retinoblastoma tumor suppressor protein (RB) binding motif in the viral oncoprotein Tax (4).This novel finding suggests that intracellular angiotensinogen physically interacts with RB and thereby inactivates it, thus leading to cellular hyperproliferation and tissue inflammation both of which ultimately contribute to pathologically increasing blood pressure.This new hypothesis on a potential involvement of angiotensinogen in the pathogenesis of hypertension is consistent with several reports on the inflammationhypertension connection (5-7) along with data showing that the pro-inflammatory cytokine interleukin 6 increases the (plasma) level of angiotensinogen (8) and, moreover, that the angiotensinogen gene is a target for the intracellular pro-inflammatory protein NF-κB (9). In this context, it is worth noting that NF-κB inactivates RB (10) and, conversely, intact RB inhibits the gene regulatory activity of NF-κB through the conformational induction of a transcriptionally inactive NF-κB-DNA complex (11).Given this now proposed candidate role for angiotensinogen in the etiology of hypertension, it should be promising to target the above-described angiotensinogen LXFXE RB-binding motif by means of antiproliferative