Role of Higenamine in Heart Diseases: A Mini-Review

Abstract

Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc. This study is aimed to clarify the role of higenamine in heart diseases. Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction. In addition, several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure. Moreover, the heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway. However, the interventional effects of higenamine on heart disease and its underlying mechanisms based on experimental studies have not yet been systematically reviewed. This paper reviewed the potential pharmacological mechanisms of higenamine on the prevention, treatment, and diagnosis of heart disease and clarified its clinical applications. The literature shows that higenamine may have a potent effect on complex heart diseases, and proves the profound medicinal value of higenamine in heart disease.

Catecholamine Derivatives: Natural Occurrence, Structural Diversity, and Biological Activity

“…179 The wide spectrum of roles of higenamine in heart diseases were reviewed thoroughly in 2022. 180 Inspired by the bioactivity reported for higenamine and to examine the traditional use of P. oleracea to treat asthma, our group hypothesized that some β 2 -ARs agonists may also exist within P. oleracea. Screening against a CHO-K1/GA15 cell line expressing β 2 -AR combined with a calcium assay, it was found that 68 and 50, together with 30, 56, 49, 64a, 54, 52, 31, 53, 55, and 51 (Table 2), were potent to moderate β 2 -AR agonists, whereas 63 and 148 were inactive.…”

“…72 was found to increase cardiac action potential and heart rate via β 1 -AR stimulation, while also preventing myocyte apoptosis and myocardial infarction through selective activation of the β 2 -AR/PI3K/AKT signaling pathway . The wide spectrum of roles of higenamine in heart diseases were reviewed thoroughly in 2022 …”

“…dimers were isolated from Periostracum Cicadae, including (2R,3S)-trans-2-(3′,4′-dihydroxyphenyl)-3-acetylamino-7-(Nacetyl-2″-aminoethyl)-1,4-benzodi-oxane-3′-O-β-D -glucopyranoside(185), (2S,3R)-trans-2-(3′,4′-dihydroxyphenyl)-3-acetylamino-7-(N-acetyl-2″-amino-1″-hydroxylethyl)-1,4-benzodioxane(186), (2R,3S)-trans-2-(3′,4′-dihydroxyphenyl)-3-acetylamino-6-(N-acetyl-2″-amino-1″-hydroxylethyl)-1,4-benzodioxane (187), (2S,3S)-cis-2-(3′,4′-dihydroxyphenyl)-3acetylamino-6-(N-acetyl-2″-aminoethyl)-1,4-benzodioxane(188), and (2S,3S)-cis-2-(3′,4′-dihydroxyphenyl)-3-acetylamino-7-(N-acetyl-2″-aminoethylene)-1,4-benzodioxane (189) 133. In 2019, two novel dopamine dimers, cicadamide A(190), and racemic cicadamide B (191) consisting of two enantiomers 191a and 191b, were identified from Periostracum Cicadae, together with known (2R,3S)-trans-2-(3′,4′-dihydroxyphenyl)-3-acetylamino-7-(N-acetyl-2″-aminoethyl)-1,4-benzodioxane (192) and (2R,3S)-trans-2-(3′,4′-dihydroxyphenyl)-3-acetylamino-6-(N-acetyl-2″-aminoethyl)-1,4-benzodioxane(180) 124. Since 2014, several novel dopamine dimers have been isolated from A. chinensis, including aspongopusamide A(177) and aspongopsamide B (193), alongside their enantiomers 177a and 177b and 193a and 193b, respectively; 120 aspongamide E (194), consisting of rare sulfonyl-containing enantiomers 194a and 194b; 125 racemic aspongdopamine A…”

Mechanism of tonifying-kidney Chinese herbal medicine in the treatment of chronic heart failure

“…Higenamine, an active component of Aconitum carmichaeli , has shown a positive effect on improving chronic heart failure. Higenamine enhanced contractility of failing hearts and improved energy metabolism in cardiomyocytes, inhibited TGF-β1/Smad signaling transduction, thereby reducing cardiac fibrosis caused by cardiac fibroblast proliferation ( 45 , 46 ). The activation of the NF-κB increases the production of inflammatory cytokines and chemokines.…”

Salsolinol improves angiotensin II‑induced myocardial fibrosis in vitro via inhibition of LSD1 through regulation of the STAT3/Notch‑1 signaling pathway

“…Aconite was widely used in ancient China to treat similar symptoms of heart failure (3). A previous study showed that the combination of water-soluble alkaloids of aconite and total ginsenosides had a therapeutic effect in a rat model of acute heart rats (4).…”