The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference series)

Abstract

Pulmonary arterial hypertension (PAH) is associated with aberrant pulmonary vascular remodeling that leads to increased pulmonary artery pressure, pulmonary vascular resistance, and right ventricular dysfunction. There is now accumulating evidence that the renin-angiotensin-aldosterone system is activated and contributes to cardiopulmonary remodeling that occurs in PAH. Increased plasma and lung tissue levels of angiotensin and aldosterone have been detected in experimental models of PAH and shown to correlate with cardiopulmonary hemodynamics and pulmonary vascular remodeling. These processes are abrogated by treatment with angiotensin receptor or mineralocorticoid receptor antagonists. At a cellular level, angiotensin and aldosterone activate oxidant stress signaling pathways that decrease levels of bioavailable nitric oxide, increase inflammation, and promote cell proliferation, migration, extracellular matrix remodeling, and fibrosis. Clinically, enhanced renin-angiotensin activity and elevated levels of aldosterone have been detected in patients with PAH, which suggests a role for angiotensin and mineralocorticoid receptor antagonists in the treatment of PAH. This review will examine the current evidence linking renin-angiotensin-aldosterone system activation to PAH with an emphasis on the cellular and molecular mechanisms that are modulated by aldosterone and may be of importance for the pathobiology of PAH.

Keywords: aldosterone; angiotensin II; mineralocorticoid receptor; pulmonary arterial hypertension; spironolactone.

Figure 1

The renin-angiotensin-aldosterone system. In response to a drop in blood pressure or sodium intake (A), renin is released from the juxtaglomerular cells of the kidney to increase angiotensin II levels (B). Angiotensin II increases blood pressure by stimulating the production of aldosterone by the adrenal gland (C) to initiate salt and water retention and vasoconstriction of systemic resistance vessels (D). ACE = angiotensin-converting enzyme.

Figure 2

Angiotensin signaling. Angiotensin II may be generated from angiotensin I by the actions of angiotensin-converting enzyme (ACE) or chymase. Angiotensin I may also be cleaved by angiotensin-converting enzyme 2 (ACE2) or neutral endopeptidase (neprilysin) to yield angiotensin-(1–7). Angiotensin II binds to the angiotensin type 1 (AT₁) receptor and the angiotensin type 2 (AT₂) receptor, which have opposing effects on vascular structure and function. In addition, angiotensin-(1–7), which binds to the Mas receptor, is considered vasculoprotective.

Figure 3

The effects of aldosterone on vascular function in pulmonary hypertension. Elevated levels of aldosterone have deleterious effects on vascular homeostasis, including increased oxidant stress resulting in a decrease in nitric oxide (NO) and endothelial dysfunction, cell swelling, and inflammation. Aldosterone also contributes to vascular remodeling by increasing cell proliferation and migration leading to vascular hypertrophy and by stimulating extracellular matrix remodeling and fibrosis. ACTH = adrenocorticotropic hormone; eNOS = endothelial isoform of nitric oxide synthase; ENaC = epithelial sodium channel; EPC = endothelial progenitor cell.