News & Research

    University of Louisville, Louisville, Kentucky

Nrf2 activator to prevent diabetic cardiomyopathy:

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes

Type of Grant: Basic Science

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Diabetes Type: Type 1 diabetes

Research Description

The heart of diabetic patients is easily damage by diabetes-caused oxidative stress. However, application of single antioxidant or increasing single gene can't protect the heart very well from diabetes; therefore, to develop a way to increase several antioxidant genes or proteins in the heart may be a better way to protect the heart from diabetes for the patients.  A transcriptional factor called Nrf2 is such a molecule that can turn on several antioxidant components in the body. The research group has demonstrated that if the mice without Nrf2, these mice were more easily damaged by diabetes. We also found that a compound (Dh404) without toxic effect can increase cardiac Nrf2 function to protect the heart from oxidative damage. Therefore, we thought that Nrf2 may play a pivotal role in up-regulation of multiple antioxidants in protecting the heart from diabetes, and we should examine whether this compound (Dh404) can become a new medicine to increase our body's Nrf2 level and function to protect the heart from diabetes. This study will prove whether Dh404 can protect the heart in diabetic mice; whether Dh404 increase Nrf2 function and whether Nrf2 is required for Dh404's cardiac protection. The last study is to further mechanistically study how Dh404 protect the heart from diabetes. Therefore, this is a very new project since we try to increase many good genes and proteins in the heart via up-regulation of Nrf2. This is also a feasible project since we have shown the importance of Nrf2 in protecting diabetic heart, and also have the compound (Dh404) to increase cardiac Nrf2 in animals.

Research Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

My project covers diabetic myocardial complications, in particular diabetic cardiomyopathy.  Specifically, the present project will address the critical role of Nrf2 a potent antioxidant in preventing diabetes-induced oxidative and nitrosative stress that induces the development of diabetic cardiomyopathy.

It is known that application of single antioxidant or increasing single gene can't protect the heart very well from diabetes; therefore, to develop a way to increase several antioxidant genes or proteins in the heart may be a better way to protect the heart from diabetes for the patients.  A transcriptional factor called Nrf2 is such a molecule that can turn on several antioxidant components in the body. The research group has demonstrated that if the mice without Nrf2, these mice were more easily damaged by diabetes. We also found that a compound (Dh404) without toxic effect can increase cardiac Nrf2 function to protect the heart from oxidative damage. Therefore, we thought that Nrf2 may play a pivotal role in up-regulation of multiple antioxidants in protecting the heart from diabetes, and we should examine whether this compound (Dh404) can become a new medicine to increase our body's Nrf2 level and function to protect the heart from diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Effective approach to preventing diabetic cardiomyopathy is not available yet. This study will prove whether Dh404 can protect the heart in diabetic mice; whether Dh404 increase Nrf2 function and whether Nrf2 is required for Dh404's cardiac protection. This is a very important project since if we proved expectations, we can find or develop some dietary supplements that can up-regulate cardiovascular levels of Nrf2, leading to up-regulation of other good genes and proteins in the heart to prevent diabetes-induced cardiovascular diseases.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

Since I graduated from medical school in 1983, I have studied the role of oxidative stress/nitrosative in the pathogenesis of various diseases and dreamed to develop clinically useful approaches to prevent or treat these diseases based on myself and other research findings.

I found that there is a tremendous increase in the incidence of diabetic patients in North American, China and the world.  Among the diabetic patients, some are my relatives and friends.  I also found that the major cause of diabetic mortality is cardiovascular complications.  In addition, a very important fact is that my mother died from cardiac dysfunction with an age of only 59 year-old in 1999, which stimulates me to specifically explore the role of oxidative stress/nitrosative in cardiovascular pathogenesis of diabetes and its prevention.  I hope that diabetic patients including my relatives and friends can be benefited from my own research.

In what direction do you see the future of diabetes research going?

I believe that through research supported by ADA and other agencies diabetes including both type I and type II will be prevented or at least delayed if early diagnosis can be developed.  For the patients who have diagnosed as diabetes the complications, such as hypertension, cardiomyopathy, and stroke would be prevented by enhancing endogenous and supplementation of exogenous antioxidants.  I believe that these approaches will be available in the future.