br Physiology of the apelin
Physiology of the apelin pathway
Role of apelin in heart disease Both apelin and apelin receptor null mice manifested moderate reduction in cardiac contractile function under basal conditions and their exercise capacity was markedly reduced (Table 1) . Apelin has direct effects on the propagation of Tacedinaline synthesis and contractility in cardiomyocytes, and the mechanisms involved in the inotropic effects may be associated with increased myofilament sensitivity to Ca (Table 1) . Pre-treatment of cardiac fibroblasts with apelin-13 inhibits Ang II-induced collagen production and activation of both connective tissue growth factor (CTGF) and transforming growth factor-β (TGF-β) (Table 1 & Fig. 2) . Apelin attenuates the osteoblastic differentiation of human aortic valve interstitial cells, suggesting that loss of apelin action promotes valvular heart disease (Table 1) . Chronic infusion of apelin 13 into the paraventricular nucleus (PVN) resulted in increased myocardial atrial natriuretic peptide and β-myosin heavy chain mRNA expression, both of which potentiated cardiac hypertrophy (Table 1), indicating the potential linkage between PVN apelin and hypertension (Table 1) . Hypertensive patients with left ventricular hypertrophy (LVH) display lower serum apelin levels compared with patients without LVH, consistent with an important role of the apelin pathway in the cardiac hypertrophic response . Heart failure is common and carries high morbidity and mortality . Improved understanding and treatment of HF has resulted in significant improvement in outcomes over the past two decades . Aged apelin mutant mice developed progressive impairment of myocardial contractility along with systolic dysfunction, and loss of apelin contributed to HF in response to pressure-overload (Table 1) . Reduction of the apelin/apelin receptor in the heart and aorta aggravates pathophysiological responses to hypertension and HF in the two-kidney, one-clip (2K1C) hypertensive rats (Table 1) . The systolic and diastolic function was dramatically improved following infusion of pyr-apelin 13 in hypertensive rats with HF (Table 1) . Administration of pyr-apelin 13 to Dahl salt-sensitive hypertensive rats with end-stage HF leads to inhibition of cardiac dysfunction and cardiovascular remodeling, accompanied by decreased expression of inflammation factors such as tumor necrosis factor-α, monocyte chemoattractant protein-1 and interleukin (IL)-1β . Apelin-mediated activation of PKCε and ERK1/2 was responsible for enhancement of cardiac contractility with myosin light chain kinase (MLCK) being the downstream target (Table 1) . While cardiomyocyte-specific apelin receptor-overexpression in mice leads to cardiac hypertrophy and contractile dysfunction, pregnancy exacerbated this phenotype resulting in HF, suggesting that excessive activation of the apelin receptor may contribute towards post-partum cardiomyopathy (Table 1) . Basal blood pressure is unaltered in apelin receptor-deficient mice. However, exogenous apelin lowers blood pressure in rodents, which was abrogated in apelin receptor-deficient mice . These effects are paralleled in humans in whom apelin peptides induce peripheral and coronary vasodilatation while increasing cardiac output and contractility . Importantly, both the local vascular and systemic hemodynamic responses to apelin are preserved in patients with stable symptomatic chronic heart failure, maintained on contemporary medical therapy , . Importantly, both the local vascular and systemic hemodynamic responses to apelin are preserved in patients with stable symptomatic chronic heart failure , . Circulating apelin levels are reduced in patients with essential hypertension, and lower plasma apelin level is independently associated with more profound left ventricular systolic and diastolic dysfunction, indicating that apelin may serve as a marker predicting an increased risk of HF (Table 1) , . Obese patients with higher left ventricular ejection fraction have greater levels of plasma apelin than non-obese patients, and in an obese murine model of ischemia/reperfusion (I/R) injury, apelin prevents nuclear translocation of FoxO3 in response to oxygen deprivation, providing insights into its potential clinical relevance in obese patients with HF . Reduced plasma and myocardial apelin levels in patients with advanced HF with concomitant reduction in expression of the apelin receptor clearly suggest that the apelin system is compromised in HF , . However, in contrast with these findings and compared with the healthy controls, no significant difference in plasma apelin levels were noted in patients with dilated cardiomyopathy . The discrepancies among these studies need to be clarified but may be related to the quality of the apelin peptide assays. The mechanism leading to the attenuation of apelin/apelin receptor system in HF may involve Ang II-induced downregulation of the synthesis and release of apelin. Indeed, genetic deletion of apelin in mice leads to cardiac dysfunction, which is abrogated by treatment with AT1 receptor blockade or by AT1 receptor knockout .