Angiotensin-Converting Enzyme 2 Negatively Regulates Apelin Peptide Effects (p 365)
Apelin is a family of endogenous peptide ligands, and mature apelin peptides are the C-terminal fragments of preproapelin. Apelin peptides have multiple cardiovascular protective effects and act via the apelin receptor. However, the therapeutic application of apelin peptides is limited by their extremely short biological half-lives. The C-terminal of apelin is critical for its interaction with its receptor and physiological action. The design and synthesis of apelin analogs that are resistant to the action of proteases represent a critical step in enhancing the therapeutic potential of apelin peptides. We showed that angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase, which hydrolyses apelin peptides at the C-termini leading to loss of the C-terminal amino acid residue, phenylalanine. Using a combination of in vivo and in vitro techniques including the genetic and pharmacological inhibition of ACE2, we demonstrated ACE2 is an important protease that removes the C-terminal phenylalanine residue, thereby functioning as a negative physiological regulator of apelin peptide physiological effects. We designed and synthesized apelin analogs that were resistant to ACE2 proteolytic action but were susceptible to the action of other plasma proteases. Our findings illustrate the importance of identifying proteases that inactivate apelin peptides and the feasibility of synthesizing apelin analogs. These results highlight a mutual regulatory interaction between ACE2 and apelin, whereby apelin positively regulates ACE2 levels as reported previously, and ACE2 which in turn partially inactivates apelin peptides, thereby constituting a negative feedback regulatory mechanism.
Metabolites Associated With Incident Hypertension (p 471)
Metabolomics is a promising tool to gain new insights into early metabolic alterations preceding the development of hypertension in humans. We therefore aimed to identify serum metabolites associated with incident hypertension in the EPIC (European Prospective Investigation into Cancer and Nutrition)-Potsdam study using the random survival forest statistical method. The study population consisted of 135 cases and 981 noncases of incident hypertension with a mean follow-up of 9.9 years. Of 127 metabolites, 6 metabolites (serine, glycine, acyl-alkyl-phosphatidylcholines C42:4 and C44:3, and diacyl-phosphatidylcholines C38:4 and C38:3) were identified to be most predictive for incident hypertension. Moreover, the identified metabolites improved prediction of incident hypertension when used together with known risk markers of hypertension. Higher concentrations of serine, glycine, and acyl-alkyl-phosphatidylcholines C42:4 and C44:3 tended to be associated with higher and diacyl-phosphatidylcholines C38:4 and C38:3 with lower predicted 10-year hypertension-free survival. In addition, some nonlinearity in the above associations were observed. This study indicates that metabolic alterations occur early in the development of hypertension. The visualized associations between identified metabolites and the predicted 10-year hypertension-free survival are useful to derive clinical cut points for clinical implications and for further clinical studies to confirm the present findings. However, the revealed metabolic alterations that were associated with incident hypertension are confined to a few members of the amino acid or phosphatidylcholine metabolism, respectively.
Magnesium and Blood Pressure (p 324)
Magnesium (Mg) is an essential mineral with multiple biological functions. There is a longstanding interest in the promising yet unproven role of Mg in the prevention of hypertension. A substantial body of basic research has accumulated for decades, implicating a pivotal role of Mg homeostasis in regulating blood pressure (BP). Growing evidence from epidemiological studies over the past 50 years also suggests that Mg intake may be a modifiable factor for hypertension. However, direct evidence from randomized clinical trials has been inconclusive because of considerable heterogeneity across trials. In particular, differences in trial quality characteristics, such as randomization, blinding design, sample size, trial duration, Mg formulation and dose, and compliance rate would potentially modify the effects of Mg on BP. In this issue, Xi Zhang et al demonstrated a reduction of BP by oral Mg supplementation based on a meta-analysis of 34 randomized double-blind placebo-controlled trials, which are considered to be “the gold standard” in human studies for establishing a cause–effect relationship. To evaluate the result robustness, they performed multiple subgroup analyses stratified by several prespecified factors and found a greater reduction in BP in trials with high quality or low dropout rate. They also evaluated changes in serum Mg levels by Mg supplementation and observed a close association with concomitant BP reduction (Figure). These findings provide strong support for a causal effect of Mg supplementation on lowering BP and for the recommendation of oral Mg supplements for primary prevention of hypertension or as adjuvant antihypertensive therapy.
- © 2016 American Heart Association, Inc.