Novel caffeic acid derivatives promote the phenotypic and functional switch of macrophages toward resolution of inflammation and cardiac regeneration after myocardial infarction

Dr Rong, Jianhui   (Principal Investigator (PI))

Professor Li Xuechen   (Co-Investigator)

Professor Han Yi Fan   (Co-Investigator)

36

2015-11-01

1059311

Novel caffeic acid derivatives promote the phenotypic and functional switch of macrophages toward resolution of inflammation and cardiac regeneration after myocardial infarction

caffeic acid derivative, iNOS, macrophages, myocardial infarction, Nrf2/HO-1

Traditional Chinese Medicine (basic)

Biology and Medicine (M)

17120915

General Research Fund (GRF)

2015

Completed

1 The first objective is to identify the actions of PACA on the phenotypes and functions of macrophages. Our pilot results suggest that PACA is the least toxic and most active compound for regulating the phenotypes and functions of macrophages. We will examine the effect of PACA on the expression of several additional biomarkers (i.g., IL-1β, TNF-α, CD68, CD206) and the functions of macrophages such as phagocytosis and chemotactic potential. We will verify the effect of PACA on phenotypes and functions of primary mouse peritoneal macrophages. 2 The second objective is to discover the mechanisms by which PACA regulates the phenotypic and functional switch of macrophages. iNOS is a useful biomarker for monitoring the phenotypes and functions of macrophages. We recently found that PACA activated Nrf2 pathway and induced antioxidant HO-1 via direct modification of Keap1. We also found that HO-1 inhibitor could attenuate the inhibitory effect of PACA on iNOS induction. Thus, this study will focus on the effect of PACA on iNOS as an indicator. We will employ siRNA, ChIP, promoter cloning and promoter-reporter system to address how different transcription factos and signaling pathways (i.g., PKC, PKA, COCS-1 and -3) regulate the expression of iNOS in response to PACA. 3 The third objective is to explore the in vivo efficacy of PACA in modulating pro-inflammatory and anti-inflammatory macrophages in rodent MI models. We found that PACA attenuated isoproterenol-induced myocardial injury by reducing NO production and increasing GSH levels. On the other hand, PACA effectively stimulated macrophages to secret chemotactic mediators for bone marrow-derived hematopoietic stem cells. Thus, we will verify whether PACA exhibits cardioprotective activity in rodent MI models by targeting macrophages. We will focus on the in vivo effects of PACA on phenotypes and functions of macrophages with a special regard to resolution of inflammation and cardiac repair.