Activation of Cannabinoid Receptor Type II by AM1241 Ameliorates Myocardial Fibrosis via Nrf2-Mediated Inhibition of TGF-β1/Smad3 Pathway in Myocardial Infarction Mice

Sep 12, 2016Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

Activating a specific cannabinoid receptor with AM1241 may reduce heart scarring after heart attack by blocking a key cell signaling pathway in mice

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

AM1241 significantly improved cardiac function and reduced fibrosis markers in mice post-myocardial infarction.

Activation of the CB2 receptor by AM1241 is associated with a decrease in collagen I and III, fibronectin, Plasminogen activator inhibitor-1, and tissue inhibitor of metalloproteinase-1.
In cardiac fibroblasts exposed to ischemic conditions, AM1241 decreased levels of α-SMA, collagen I, and collagen III.
The effects of AM1241 on fibrosis markers were partially diminished when Nrf2 was inhibited using siRNA.
AM1241 enhanced the movement of Nrf2 to the nucleus and inhibited the TGF-β1/Smad3 pathway in a manner dependent on Nrf2.

AI simplified

AIMS: Myocardial interstitial fibrosis is a major histologic landmark resulting in cardiac dysfunction after myocardial infarction (MI). Activation of cannabinoid receptor type II (CB2 receptor) have been demonstrated to reduce fibrosis in hepatic cirrhotic rat. However, the anti-fibrotic effect of CB2 receptor activation in infarcted hearts was still unclear. In this study, we aimed to investigate the effects of a CB2 receptor selective agonist AM1241 on myocardial fibrosis post MI in mice.

METHODS: Echocardiograph was conducted to assess cardiac function. Fibrosis markers such as type I and type III collagen, fibronectin, Plasminogen activator inhibitor(PAI)-1 and tissue inhibitor of metalloprotease(TIMP)-1 were examined by Western blot, while collagens were directly observed by Sirius-red staining. Primary cultured cardiac fibroblasts(CFs) were subjected to hypoxia/serum deprivation (H/SD) injury to simulate ischemic conditions in vivo. Nrf2 siRNA were applied to explore the role of Nrf2 and TGF-β1/Smad3 pathway in this process.

RESULTS: Echocardiography showed that AM1241 significantly improved cardiac function, suppressed the expression of fibrosis markers such as collagen I and collagen III, fibronectin, PAI-1 and TIMP-1 in mice with MI. In cardiac fibroblasts subjected to H/SD injury, AM1241 reduced the elevated levels of α-SMA, collagen I and collagen III, which were partially abrogated by the Nrf2 siRNA transfection. Furthermore, AM1241 not only activated and accelerated the translocation of Nrf2 to nucleus, but also inhibited TGF-β1/ Smad3 pathway in an Nrf2 dependent manner.

CONCLUSION: CB2 receptor agonist AM1241 alleviated myocardial interstitial fibrosis via Nrf2 -mediated down-regulation of TGF-β1/Smad3 pathway, which suggested that CB2 receptor activation might represent a promising target for retarding cardiac fibrosis after MI.

Full Text

Full text is available at the source.

View full text ↗View full text (PDF) ↗

Activation of Cannabinoid Receptor Type II by AM1241 Ameliorates Myocardial Fibrosis via Nrf2-Mediated Inhibition of TGF-β1/Smad3 Pathway in Myocardial Infarction Mice

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief