A Novel Modulator of the Renin–Angiotensin System, Benzoylaconitine, Attenuates Hypertension by Targeting ACE/ACE2 in Enhancing Vasodilation and Alleviating Vascular Inflammation

Abstract

The monoester alkaloids in Aconitum carmichaelii, including benzoylaconitine (BAC), benzoylmesaconine, and benzoylhypaconitine, were found to have anti-hypertensive effects in spontaneously hypertension rats (SHRs), of which BAC is the strongest. However, its antihypertensive target and underlying molecular mechanisms remain unclear. In this study, first, we screened the antihypertensive targets of BAC by using the CVDPlatform (www.cbligand.org/CVD) and found that ACE/ACE2 are the most possible targets. Then, we verified the effect of BAC on ACE/ACE2 by virtual docking, SPR, enzyme activity assay, and HUVECs cell experiment. We found that BAC could bind with ACE/ACE2, inhibit ACE activity and protein expression, and activate ACE2 enzyme activity. Using vascular function test in vitro, we found that BAC could target ACE/ACE2 to enhance endothelium-dependent vasorelaxation. In BAC-treated SHRs, the levels of ACE and AngII in serum were reduced while Ang (1–7) was increased significantly, and the expression of ACE was reduced, which suggested that BAC can inhibit ACE and activate ACE2 to inhibit AngI to AngII and promote AngII to Ang (1–7) to inhibit vasoconstriction and finally attenuate hypertension. Furthermore, the signaling pathways with regard to vasorelaxation and vascular inflammation were investigated. The results showed that BAC could significantly activate Akt/eNOS, increase NO production, and promote endothelial-related vasodilation; BAC could also reduce inflammatory factors TNF-α and IL6, inhibition of COX-2 expression, and IKB-α phosphorylation to reduce vascular inflammation in SHRs. In brief, BAC targets ACE/ACE2 to enhance endothelium-dependent vasorelaxation and reduce vascular inflammation to attenuate hypertension as a potential modulator of the renin–angiotensin system.

Novel Multitarget ACE Inhibitory Peptides from Bovine Colostrum Immunoglobulin G: Cellular Transport, Efficacy in Regulating Endothelial Dysfunction, and Network Pharmacology Studies

“…In KKS, ACE hydrolyzes bradykinin, a vasodilatory peptide, into inactive fragments. 2,3,8,9 Hence, inhibiting ACE activity can reduce Ang II levels and increase bradykinin levels, resulting in a hypotensive effect. The use of ACE inhibitors in the prevention and treatment of hypertension has been extensively studied.…”

“…In RAS, ACE cleaves inactive angiotensin I (Ang I) into a His-Leu dipeptide and angiotensin II (Ang II), which exhibits strong vasoconstrictive activity. In KKS, ACE hydrolyzes bradykinin, a vasodilatory peptide, into inactive fragments. ,,, Hence, inhibiting ACE activity can reduce Ang II levels and increase bradykinin levels, resulting in a hypotensive effect. The use of ACE inhibitors in the prevention and treatment of hypertension has been extensively studied.…”

Benzoylaconine Protects Skeletal Muscle Against Ischemia-Reperfusion Injury Through Activation of IF1-Dependent AMPK/Nrf2 Axis

“…The processed lateral root of Aconitum carmichaelii Debeaux (Ranunculaceae), commonly known as "Fuzi", has been officially documented in the Chinese pharmacopoeia with an extended history of usage in traditional Chinese medicine. 6 Its traditional applications include treating cardiovascular diseases and relieving pain, cold, and numbness of limb muscles (Bi Zheng). The alkaloids present in Aconitum carmichaelii Debeaux are considered to be the most predominant active ingredients.…”

“…In our previous studies, we conducted a screening of bioactive alkaloids in Aconitum carmichaelii Debeaux and found that benzoylaconine (BAC) exhibited significant anti-hypertensive and anti-heart failure effects. 6,7 Additionally, other scholars have demonstrated the significant pharmacological potential of BAC, including analgesic, anti-inflammatory, and anti-tumor properties. 8,9 Furthermore, our systematic analysis revealed that BAC is the main monoester-diterpenoid alkaloid after boiling and metabolism.…”

Serum ACE2 Level is Associated With Severe SARS-CoV-2 Infection: A Cross-Sectional Observational Study

“…14 On the other hand, high ACE2 levels have been linked with an increased inflammatory burden. 15 Therefore, ACE2 levels could be associated with Covid-19 related inflammation.…”