Targeting the Elabela/Apelin-Apelin Receptor Axis as a Novel Therapeutic Approach for Hypertension
Hypertension, characterized by elevated systemic arterial blood pressure, is a leading risk factor for global mortality and morbidity. It significantly increases the likelihood of severe cardiovascular and cerebrovascular complications. The renin-angiotensin system (RAS) and the elabela/apelin-apelin receptor (APJ) axis are closely linked to the pathophysiology of hypertension. The elabela/apelin-APJ axis plays a crucial role in regulating blood pressure, vascular tone, and cardiovascular dysfunction by counteracting the angiotensin II/angiotensin II type 1 receptor (AT1R) axis and enhancing endothelial nitric oxide (NO) synthase/NO signaling. This axis also exerts beneficial effects on angiogenesis, cellular proliferation, fibrosis, apoptosis, oxidative stress, and cardiovascular remodeling during hypertension. The diverse functions of the elabela/apelin-APJ axis in different blood vessel types and pathological conditions highlight its potential as a therapeutic target. This review explores the physiology, biochemistry, and mechanisms of the elabela/apelin-APJ axis, emphasizing its role in hypertension and hypertensive cardiovascular injury, and proposes it as a novel therapeutic strategy.
The elabela/apelin-APJ axis is involved in various cardiovascular processes, including vascular tone regulation, heart contraction, angiogenesis, endoderm differentiation, and heart morphogenesis. APJ, a G-protein coupled receptor, was first discovered in 1993 and is conserved across species. Apelin, identified in 1998, was initially thought to be the sole ligand for APJ. However, the discovery of elabela, a novel endogenous ligand, has expanded our understanding of this axis. Both elabela and apelin are widely expressed in the cardiovascular system and have distinct isoforms with varying tissue distribution, potency, and receptor binding affinity. The elabela/apelin-APJ axis demonstrates a regulatory role in cardiovascular physiology and pathophysiology, making it a potential target for cardiovascular drug discovery.
The elabela/apelin-APJ axis plays a critical role in blood pressure regulation. Studies have shown that circulating levels of elabela and apelin are reduced in patients with essential hypertension, and their administration can lower blood pressure in hypertensive animal models. Elabela induces vasodilation in coronary arteries and reverses vasopressor responses in pulmonary arterial hypertension and angiotensin II-induced hypertension. Mechanistically, elabela-induced relaxation in isolated mouse aorta is NO-independent, suggesting other pathways are involved. Apelin, on the other hand, promotes vasodilation via NO-dependent mechanisms, increasing NO production and inhibiting vascular smooth muscle cell (VSMC) calcification. Apelin also attenuates abnormal angiotensin II-induced contraction in intrarenal arteries through PI3K/AKT/endothelial NO synthase signaling.
The interaction between the elabela/apelin-APJ axis and RAS is significant in hypertension. The elabela/apelin-APJ axis counterbalances RAS activation by regulating the ratio of angiotensin-converting enzyme 2 (ACE2) to ACE and prorenin receptor to soluble prorenin receptor. It also forms heterodimers with AT1R, preventing angiotensin II binding and enhancing NO-dependent signaling. APJ is often co-expressed with AT1R and acts as an endogenous counter-regulator in the blood vessel wall. Reduced APJ expression in hypertensive rats further underscores its protective role.
Despite the predominantly hypotensive effects of apelin, some studies report blood pressure elevation following its administration. This biphasic response may be related to high doses of apelin, compensatory mechanisms, or endothelial dysfunction. Apelin can cause vasoconstriction in damaged endothelial cells, and its effects on blood pressure may vary depending on the vascular bed and underlying conditions. Central apelin administration increases blood pressure through nicotinamide adenine dinucleotide phosphate oxidase-dependent superoxide formation and myosin light chain phosphorylation. The interaction between APJ and α1-adrenergic receptors also contributes to vasoconstriction, although the molecular mechanisms remain poorly understood.
The elabela/apelin-APJ axis has protective effects in hypertensive cardiovascular injury. Reduced elabela levels are associated with hypertension-related vascular damage, and exogenous elabela can reverse angiotensin II-mediated apoptosis and autophagy imbalance in rat aortic adventitial fibroblasts. Elabela deficiency promotes pre-eclampsia and cardiovascular malformations, while its administration alleviates these symptoms. Apelin levels are also reduced in essential hypertensive patients and those with aortic valve stenosis. Apelin restores declining heart function and accelerates VSMC proliferation through PI3K/AKT/extracellular signal-regulated kinase and Jagged-1/Notch3 signaling pathways. In contrast, apelin reduces pulmonary VSMC proliferation in hypoxic conditions via PI3K/AKT/mammalian target of rapamycin signaling.
Apelin increases NO formation to counteract superoxide-induced vascular wall changes and attenuates angiotensin II-induced atherosclerosis in ApoE knockout mice. The apelin-APJ axis upregulates ACE2 expression in failing hearts, enhancing the conversion of angiotensin II to angiotensin 1–7. Elabela, however, protects against pressure-overload-induced heart failure by suppressing ACE. The elabela/apelin-APJ axis also mediates atherosclerosis, with apelin gene expression upregulated in atherosclerotic plaques. Its involvement in VSMC and endothelial cell regulation highlights its complex role in hypertensive conditions.
In conclusion, the elabela/apelin-APJ axis is a promising therapeutic target for hypertension and hypertensive cardiovascular dysfunction. Its role in regulating vascular tone, counteracting RAS, and protecting against cardiovascular injury underscores its potential in developing novel anti-hypertensive drugs. Further research is needed to elucidate the underlying mechanisms and optimize pharmacological interventions to achieve long-term blood pressure reduction and improve hypertensive organ damage. Targeting the elabela/apelin-APJ axis offers a novel approach to reducing mortality and healthcare costs associated with hypertension worldwide. doi.org/10.1097/CM9.0000000000001766
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