Monocyte chemoattractant protein-1: a key mediator of angiotensin II-induced target organ damage in hypertensive heart disease?

Hypertension is a leading risk factor for the development and progression of cardiovascular diseases. If it is left untreated, it often leads to target organ damage in resistance blood vessels, as well as the heart and kidney [1,2]. The prevalence of hypertensive vascular, heart and renal diseases is steadily increasing at an alarming rate both in the USA and worldwide. To prevent such a hypertension epidemic and/or treat target organ damage, several classes of therapeutic drugs including diuretics, β-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors (ACEI) have been developed and widely used over the last few decades [3]. In recent years a new class of compounds, angiotensin II type 1 (AT1) receptor antagonists (ARB), has been added to the roster of antihypertensive agents [4]. Although most anti-hypertensive drugs are effective in treating certain experimental models of hypertension or hypertensive patients, the effectiveness and mechanisms of their actions are markedly different [3]. However, clinical trials have suggested that ACEI and ARB may be the drugs of choice in treating hypertension, cardiac hypertrophy and congestive heart disease, in which a circulating and tissue renin–angiotensin system (RAS) may be activated [5,6]. ACEI specifically block formation of the active molecule angiotensin II at the circulating and local tissue levels, whereas ARB block its actions at the AT1 receptor level [5,6]. However, the cellular mechanisms by which ACEI and ARB exert their beneficial effects are not fully understood. The classic view is that the antihypertensive effects of ACEI and ARB are mediated at least partially, if not entirely, by lowering blood pressure and thus eliminating haemodynamic stimuli common to the disease process. However, evidence is also mounting that merely lowering blood pressure is not sufficient to account for the overall benefits of ACEI and ARB in treating hypertension and preventing target organ damage, because these benefits have been demonstrated in both animal and human studies with or without significant blood pressure-lowering effects [1,3–6]. In this issue of the journal, Behr et al. [7] report that long-term therapy with the AT1 receptor blocker eprosartan markedly reduced cardiac hypertrophy, decreased morbidity and mortality, and therefore improved overall cardiac performance in a rat model of high-salt, high-fat hypertensive heart disease, stroke-prone spontaneously hypertensive rats (SHR-SP). In their study, the beneficial effects of eprosartan were associated with significant reductions in myocardial pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) expression and production, with subsequent inhibition of monocyte and macrophage infiltration of the left ventricle [7]. Because only one-half the conventional dose of eprosartan was used, high blood pressure persisted in all three groups of SHR-SP rats with or without a high-salt, high-fat diet or eprosartan. Nevertheless, only the rats that received eprosartan exhibited decreases in MCP-1 mRNA expression and protein production, inhibition of monocyte and macrophage infiltration, and improvement of overall cardiac function [7]. Therefore, these novel findings suggest that increased MCP-1 expression may be a key mediator between angiotensin II and target organ damage in hypertensive heart disease.