Context-dependent effects of the angiotensin II type 2 receptor gene on left ventricular remodelling: the story continues

Angiotensin II and aldosterone, the effector hormones of the renin–angiotensin–aldosterone system (RAAS), play an important role in the regulation of sodium and water homeostasis, the modulation of sympathetic nervous activity and the pathogenesis of hypertension and cardiac hypertrophy and remodelling. Although the RAAS was originally regarded as a circulating system, many of its components are also present in tissues, including the heart [1]. Angiotensin II exerts its biologic effects via specific type 1 and type 2 receptors (AT1 and AT2). The AT1 receptor mediates most of the known functions of the RAAS, such as vasoconstriction, antinatriuresis, cell proliferation and liberation of catecholamines from sympathetic nerve endings and from the adrenal medulla [2]. The exact signalling pathways and the functional role of the AT2 receptors remain unclear. Recent findings suggest that the pathway involves activation of protein phosphatases, protein dephosphorylation, the nitric oxide–cGMP system and phospholipase A2 [3]. Activation of various phosphatases leads to inactivation of extracellular signal-regulated kinases, opening of K+ channels and inhibition of T-type Ca2+ channels. Thus, AT2 receptors probably counterbalance the vasoconstricting and antinatriuretic effects produced by angiotensin II via AT1 receptors [4]. AT1 and AT2 receptors are involved in pathophysiological processes such as cardiovascular remodelling following myocardial infarction and/or hypertension [5]. The effectiveness of angiotensin-converting enzyme (ACE) inhibitors [6] and AT1 receptors blockers [7] in attenuating unfavourable cardiac remodelling in patients after myocardial infarction indicates an important role of angiotensin II signalling in this process. Several experimental studies showed that AT2 receptor stimulation might play a cardioprotective role [8]. After myocardial infarction, transgenic mice lacking the AT2 receptor have higher short-term mortality and heart failure rates compared with wild-type mice [9]. Moreover, the levels of various RAAS components are altered in cardiac tissues after myocardial infarction and dynamic changes in the expression of AT1 and AT2 receptors have been recently reported [10]. A more detailed understanding of how the differential AT1 and AT2 expression and the receptors interaction cause myocardial remodelling in cardiac disease such as myocardial infarction and heart failure is of significant therapeutic interest. Considering the known pathophysiological role of the circulating and tissue RAAS in heart remodelling, genetic polymorphisms of RAAS components are prime candidates for further study in relation to cardiac morphology and function. In the current issue of the journal, Huber et al.[11] studied the associations between left ventricular phenotypes and the common polymorphisms of AT2 receptor gene. The AT2 receptor gene maps to the X-chromosome and comprises two noncoding exons, two introns and a third exon which harbours the entire open reading frame of the AT2 receptor [12]. Regulatory elements of the transcription of AT2 receptor gene are located in the promoter area and in the first intron [13]. The authors mainly focused on the most studied so far polymorphism of the AT2 receptor gene (+1675G/A), which is located in intron 1 and is likely to be functional in such a way that the G allele might be associated with increased transcription of the AT2 receptor gene and, therefore, with an increased number of AT2 receptors. Indeed, previously published studies support the hypothesis that the +1675G/A polymorphism influence left ventricular mass and that salt intake might modulate this genetic effect in the general population [14] or in hypertensive patients [15]. The authors further explored the role of the +1675G/A polymorphism on left ventricular structure in a cross-sectional manner in selected hypertensive patients who had a history of cardiovascular disease, such as coronary artery disease, myocardial infarction, stroke or peripheral artery disease, and who participated in a rehabilitation programme in 15 clinical centres across Germany [11]. The study cohort (n = 1238) includes predominantly male patients (83%). The main conclusion of the study was that the common polymorphism in the AT2 receptor gene has no impact on left ventricular mass or geometry in treated hypertensive men with or without myocardial infarction. The authors reported only minor effect of the study polymorphism on interventricular septum thickness in women [11]. The authors stated that the potential impact of the AT2 receptor gene polymorphism may be blunted by ‘other’ factors affecting left ventricular structure in treated hypertensive patients with cardiovascular disease [11]. Although the current study [11] is of undoubted interest and raises important issues for future investigation, its negative findings have to be interpreted within the context of this study's potential limitations. First, echocardiographic evaluation of left ventricular structure and function particularly in patients with myocardial infarction is prone to measurement error. In the current study, 15 centres across Germany recruited patients. It is unclear from methods how many observers performed echocardiography in each centre, whether echocardiographic readings were performed on-line or off-line and how the quality control of echocardiographic phenotypes has been organized within the study. It is obvious that in some cases of heart remodelling after myocardial infarction or cardiac surgery (thickening or thinning of the basal part of septum and/or posterior left ventricular wall), the current formula for the calculation of echocardiographic left ventricular mass cannot be simply applied. What did the observers do when left ventricular mass could not be correctly determined using M-mode echocardiography? Second, patients with ejection fraction less than 40% were excluded from the study. Thus, the authors missed the severe and the most interesting cases of left ventricular remodelling and dysfunction caused by myocardial infarction and hypertension. In this context, it is worth mentioning that the beneficial effect of treatment with ACE inhibitors and AT1 receptor blockers on left ventricular volumes and cardiac remodelling was observed mainly in postinfarct patients with severely reduced left ventricular ejection fraction (<45%) [6,7]. Moreover, the authors did not report how many patients were screened and how many were finally recruited in the study. Third, the expression of the AT2 receptor gene could be affected by the stage of the disease, treatment status and might be further modulated by environmental factors such as salt intake. The authors unfortunately did not measure sodium excretion in the study population, thus, they could not address the issue of context dependency of the AT2 receptor gene in relation to cardiac remodelling in patients with cardiac disease. Ninety-eight percent of the study population were on treatment; thus, it was impossible to study an impact of treatment on left ventricular remodelling in relation to the common AT2 receptor polymorphism. Finally, as suggested by numerous experimental studies, the AT1 and AT2 receptor expressions as well as various RAAS components are altered in cardiac tissues in response to myocardial infarction or hypertension [5,10]. Unfortunately the authors did not provide the readers with a more complete picture of polymorphisms in several common genes along the renin–angiotensin–aldosterone axis on left ventricular structure and function in patients with cardiac disease and did not investigate possible interactions between these polymorphisms. Perspectives Left ventricular hypertrophy and remodelling is a frequent complication of hypertension and other conditions such as myocardial infarction, and it is an independent predictor of a dismal cardiovascular outcome. The last decade witnessed fast progress in high-throughput genomics and proteomics and our understanding that multiple genes, interaction among genes and numerous single-nucleotide polymorphisms influence complex traits such as left ventricular morphology and function. Moreover, as exemplified by the numerous experimental studies, pathophysiological processes might modify the expression of genes and their action and interactions. Longitudinal clinical and epidemiological studies which address association between the phenotype of interest and genes related to specific pathway will increasingly become a cornerstone in the management of the flood of information produced by molecular biologists from in-vivo experiments, cell models and genetically engineered animals and will help to distinguish what is clinically relevant in experimental medicine. Acknowledgements The European Union (grants IC15-CT98-0329-EPOGH and LSHM-CT-2006-037093]) and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (grants G.0734.09 and G.0575.06) gave support to the Studies Coordinating Centre.