Abstract
BackgroundHypertension is considered the most serious risk factor for cardiovascular disease. Angiotensin-converting enzyme inhibitory peptides (ACEIPs), which are made from tuna frame protein (TFP) and yellow fin sole frame protein (YFP), have been used previously to treat hypertension. However, the production of these short peptides is usually dependent on enzymatic hydrolysis, resulting in a digested mixture that makes it difficult to purify the ACEIPs. Although it has been reported that ACEIPs could be produced in recombinant Escherichia coli strains, the use of lactic acid bacteria in the production of ACEIPs has not been demonstrated.ResultsIn this study, the ACEIP coding sequences from TFP and YFP were joined through an arginine linker and expressed in the Lactobacillus plantarum (Lb. plantarum) NC8 strain by an inducible vector pSIP-409. Then, the antihypertensive effects were determined in the model of spontaneously hypertensive rats (SHRs) by measuring the blood pressure, hematology, blood biochemistry and nitric oxide (NO), endothelin (ET) and angiotensin II (Ang II) levels. The results showed that oral administration of recombinant Lb. plantarum NC8 (RLP) significantly decreased systolic blood pressure (P < 0.01) during treatment, which lasted for at least 10 days after the last dose. Furthermore, the presence of RLP resulted in an increased level of NO, as well as decreased levels of ET and Ang II in plasma, heart, and kidney. In addition, a dramatically decreased triglyceride level was also observed even though there was no significant change in hematology or blood biochemistry. Although some drawbacks were still observed, such as the presence of an antibiotic selection marker, no obvious side effects or bacterial translocation were observed in vivo, indicating the potential application of RLP in the treatment of hypertension.ConclusionThese results demonstrated the effectiveness and safety of RLP on the treatment of hypertension.
Highlights
Hypertension is considered the most serious risk factor for cardiovascular disease
After digestion by NcoI and HindIII, the gusA gene present in pSIP409 was replaced with genes encoding an angiotensin converting enzyme inhibitory peptides (ACEIP) fusion protein, which was confirmed by restriction endonuclease digestion and sequencing, yielding the recombinant expression vector pSIP409-ACEIP (Fig. 1b)
The results showed that the systolic blood pressure (SBP) in the recombinant Lb. plantarum NC8 (RLP)-treated group decreased dramatically as time elapsed, with the lowest value of 167.111 ± 3.418 mmHg occurring on the 15th day, which was significantly lower (P < 0.01) than the 184.810 ± 4.305 mmHg in the Lb. plantarum group and the 197.443 ± 3.893 mmHg in the PBS group
Summary
Hypertension is considered the most serious risk factor for cardiovascular disease. Angiotensin-converting enzyme inhibitory peptides (ACEIPs), which are made from tuna frame protein (TFP) and yellow fin sole frame protein (YFP), have been used previously to treat hypertension. A series of natural ACE inhibitory peptides (ACEIPs) have been produced either by protein hydrolysis [18] or recombinant technologies [19, 20] without any obvious side effects, indicating their great application potential. One of these ACEIPs belongs to the family of the yellowfin sole (Limanda aspera) frame protein (YFP), with a molecular mass of 1.3 kDa and 11 amino acids. Similar beneficial effects were observed during a study in which a 21-amino-acid peptide from tuna frame protein (TFP) dramatically decreased blood pressure in the SHR model [22]
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