Pinoresinol diglucoside (PDG) attenuates cardiac hypertrophy via AKT/mTOR/NF-κB signaling in pressure overload-induced rats.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Pinoresinol diglucoside (PDG), the active compound extracted from Eucommia ulmoides, Styrax sp. and Forsythia suspensa, plays the roles in regulating hypertension, inflammation and oxidative stress.

AIMS:

Considering that hypertension and inflammation has been proved to contribute to cardiac remodeling, we tested the effects of PDG on cardiac hypertrophy (CM).

METHODS:

Male Sprague Dawley (SD) rats were used to construct hypertrophic rats by partial abdominal aortic constriction (AAC)-surgery. PDG solution (2 mg/ml) was used to treat AAC-induced rats by intraperitoneal injection at low dose (L-PDG, 2.5 mg/kg per day), medium dose (M-PDG, 5 mg/kg per day), and high dose (H-PDG, 7.5 mg/kg per day) for 3 weeks post AAC-surgery. CM was evaluated by the ratio of left ventricular weight to body weight ratio (LVW/BW), left ventricular wall thickness by H&E staining, and collagen content deposit by Masson's staining. Further, isoproterenol (ISO) and phenylephrine (PE) were used to produce cellular models of CM in neonatal rat ventricular cardiomyocytes (NRVMs). PDG pre-treated NRVMs 2 h at low dose (L-PDG, 2.5 μg/ml), medium dose (M-PDG, 5 μg/ml), and high dose (H-PDG, 7.5 μg/ml) for 24 h with or without PE- and ISO-stimulation. CM was evaluated by the expressions of hypertrophic biomarkers. Next, the hypertrophic biomarkers and pro-inflammatory cytokines were measured using quantitative real-time PCR (qRT-PCR), the expressions of protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/transcription factor nuclear factor-kappa B (NF-kB) signaling pathway were determined by Western blotting.

RESULTS:

PDG treatment prevented cardiac histomorphology damages, decreased upregulations of hypertrophic biomarkers, and prevented fibrosis and inflammation after pressure overload resulting from AAC-surgery. Consistently, PDG remarkably inhibited the changes of cardiomyocyte hypertrophic biomarkers and inflammatory responses in cellular models of CM. Interestingly, PDG administration inhibited the activation of AKT/mTOR/NF-kB signaling pathway both in vivo and in vitro.

CONCLUSIONS:

PDG prevents AAC-induced CM in vivo, PE- and ISO-induced CM in vitro. The AKT/mTOR/NF-kB signaling pathway could be the potential therapeutic target involved in the protection of PDG. These findings provide novel evidence that PDG might be a promising therapeutic strategy for CM.

• Authors: Yusha Chen, Ruiyan Pan, Juanjuan Zhang, Tianming Liang, Juan Guo, Tai Sun, Xiaoyan Fu, Ling Wang, Lane Zhang
• Journal: Journal of ethnopharmacology (J Ethnopharmacol) Vol. 272 Pg. 113920 (May 23 2021) ISSN: 1872-7573 [Electronic] Ireland
• PMID: 33607200 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Lignans
• NF-kappa B
• Phenylephrine
• pinoresinol diglucoside
• mTOR protein, rat
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Isoproterenol

Topics

• Animals
• Animals, Newborn
• Aorta, Abdominal (surgery)
• Cardiomegaly (drug therapy, etiology, pathology)
• Constriction, Pathologic
• Disease Models, Animal
• Fibrosis (prevention & control)
• Inflammation (prevention & control)
• Isoproterenol (toxicity)
• Lignans (pharmacokinetics, therapeutic use)
• Male
• Myocytes, Cardiac (drug effects)
• NF-kappa B (metabolism)
• Phenylephrine (toxicity)
• Pressure
• Primary Cell Culture
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Ventricular Remodeling (drug effects)