Hypertension has become a significant global public health concern and is also one of the most common risk factors of cardiovascular disease. Recent studies have shown the promising result of peptides inhibiting angiotensin converting enzyme (ACE) in lowering the blood pressure in both animal models and humans. However, the oral bioavailability and continuous antihypertensive effectiveness require further optimization. Novel nanoparticle-based drug delivery systems are helpful to overcome these barriers. Therefore, a poly-(lactic-co-glycolic) acid nanoparticle (PLGANPs) oral delivery system, of the antihypertensive small peptides Val-Leu-Pro-Val-Pro (VLPVP, VP5) model, was developed in this study and its antihypertensive effect was investigated in spontaneously hypertensive rats (SHRs) for the first time. The obtained VP5 nanoparticles (VP5-NPs) showed a small particle size of 223.7 ± 2.3 nm and high entrapment efficiency (EE%) of 87.37% ± 0.92%. Transmission electronic microscopy (TEM) analysis showed that the nanoparticles were spherical and homogeneous. The optimal preparation of VP5-NPs exhibited sustained release of VP5 in vitro and a 96 h long-term antihypertensive effect with enhanced efficacy in vivo. This study illustrated that PLGANPs might be an optimal formulation for oral delivery of antihypertensive small peptides and VP5-NPs might be worthy of further development and use as a potential therapeutic strategy for hypertension in the future.

Antihypertensive peptides (AHTPs) are a group of small peptides with the main role to block key enzymes or receptors in the angiotensin genesis pathway. A great number of AHTPs have been isolated or digested from natural food resources; however, comprehensive studies on comparisons of AHTPs in various species from the perspective of big data are rare. Here, we established a simplified local AHTP database, and performed in situ mapping for high throughput identification of AHTPs with high antihypertensive activity from high-quality whole proteome datasets of 18 fish species. In the 35 identified AHTPs with reported high activity, we observed that Gly-Leu-Pro, Leu-Pro-Gly, and Val-Ser-Val are the major components of fish proteins, and AHTP hit numbers in various species demonstrated a similar distributing pattern. Interestingly, Atlantic salmon (Salmo salar) is in possession of far more abundant AHTPs compared with other fish species. In addition, collagen subunit protein is the largest group with more matching AHTPs. Further exploration of two collagen subunits (col4a5 and col8a1) in more fish species suggested that the hit pattern of these conserved proteins among teleost is almost the same, and their phylogeny is consistent with the evolution of these fish species. In summary, our present study provides basic information for the relationship of AHTPs with fish proteins, which sheds light on rapid discovery of marine drugs or food additives from fish protein hydrolysates to alleviate hypertension.

Angiotensin-converting enzymes, ACE and ACE2, are two main elements in the renin–angiotensin system, with a crucial role in the regulation of blood pressure in vertebrates. Previous studies paid much attention to their physiological functions in model organisms, whereas the studies on other animals and related evolution have been sparse. Our present study performed a comprehensive genomic investigation on ace and ace2 genes in vertebrates. We successfully extracted the nucleotide sequences of ace and ace2 genes from high-quality genome assemblies of 36 representative vertebrates. After construction of their evolutionary tree, we observed that most of the phylogenetic positions are consistent with the species tree; however, certain differences appear in coelacanths and frogs, which may suggest a very slow evolutionary rate in the initial evolution of ace and ace2 in vertebrates. We further compared evolutionary rates within the entire sequences of ace and ace2, and determined that ace2 evolved slightly faster than ace. Meanwhile, we counted that the exon numbers of ace and ace2 in vertebrates are usually 25 and 18 respectively, while certain species may occur exon fusion or disruption to decrease or increase their exon numbers. Interestingly, we found three homologous regions between ace and ace2, suggesting existence of gene duplication during their evolutionary process. In summary, this report provides novel insights into vertebrate ace and ace2 genes through a series of genomic and molecular comparisons.