An overview of the mechanisms and novel roles of Nrf2 in cardiovascular diseases

ABSTRACT

Introduction: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper (bZIP) transcription factor of the cap’n’collar (CNC) family that is present in various organs. The cardiovascular system (CVS) is susceptible to a spectrum of diseases that are strongly associated with increased risks of mortality and morbidity, and studies have demonstrated that Nrf2 has a pivotal role in protection against cardiovascular diseases (CVDs).

Areas covered: Nrf2 is a basic protective molecule that guards against CVD by attenuating oxidative stress, mitochondrial dysfunction, and inflammation. Initially, we briefly introduce the biological characteristics of Nrf2 and the newly discovered Neh7 domain. Next, we discuss the concrete roles of Nrf2 in the CVS and enumerate some related upstream molecules and downstream targets. Lastly, we expand our focus to the behaviors of Nrf2 in CVDs and discuss potential research directions.

Expert opinion: Although certain studies have cast doubt on the positive actions of Nrf2 in the CVS, Nrf2 is a pivotal endogenous molecule for defense against CVD. The review compiled here may serve as a broad and comprehensive reference for the roles of Nrf2 in the CVS, with the aim of facilitating the design of new drugs and clinical therapies for CVDs.

KEYWORDS:

• Nuclear factor erythroid 2-related factor 2
• cardiovascular system
• potential research directions
• oxidative stress

Article highlights

• Nrf2 is a basic leucine zipper (bZIP) transcription factor of the cap’n’collar (CNC) family.

• Nrf2 can confer protection by regulating a series of downstream molecules, including hemeoxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase-1 (NQO1), and nuclear factor-κB (NF-κB).

• The Neh7 domain is a newly identified domain that lies between the Neh5 and Neh6 domains. The interaction between the Neh7 domain and 9-cis RA can suppress Nrf2 activity.

• Nrf2 can act as a protective molecule in myocardial ischemia, atherosclerosis, hypertension, HF, cardiomyopathy, and CKD.

• Published studies have demonstrated that over-accumulation or over-expression of Nrf2 is harmful and even sometimes lethal.

• Exercise can activate the endogenous Nrf2 pathway and protect against cardiac ischemic injury via a non-pharmacotherapy.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81422004, 81500263, 81470480, 81470477, 81100137, 81100081), the China Postdoctoral Science Foundation (2015M572681), the National High-tech R&D Program of China (2014AA020514, 2015AA020919), and the Technological New Star Program of Shaanxi Province (2014KJXX-56).