The major goal of my research is to investigate novel pathophysiological mechanisms of heart failure at whole animal, organ, cellular and molecular levels, with applications to improve therapy and survival. Studies are focused on heart failure following myocardial infarction (MI), cardiac dysfunction during endotoxemia, and embryonic heart development during maternal diabetes. Genetically altered mice are employed to elucidate the contribution of specific molecules in the disease process.
1. Nitric Oxide and Heart Development
Endothelial nitric oxide synthase (eNOS) is expressed early during heart development (E9.5) in mice. However, its role in cardiac development is not clear. We were the first to show that eNOS is pivotal to normal heart development. Mice deficient in the eNOS gene develop congenital septal defects and heart failure, leading to a high mortality after birth. This article was published in Circulation and featured on the journalís cover on August 13, 2002. Further to this work, we showed that eNOS is important in myocardial angiogenesis. Additionally, fetal myocardial eNOS expression promotes cardiomyocyte proliferation and maturation during heart development. Importantly, we demonstrated that the effects of eNOS on cardiomyocyte proliferation are through inhibition of TIMP-3 (tissue inhibitor of metalloproteinase-3), which decreases cardiomyocyte proliferation. These studies have increased our understanding on the important role of eNOS in normal heart. Ongoing research is to study the role of eNOS in cardiac malformation induced by maternal diabetes.
2. Role of Nitric Oxide in Heart Failure
A major research focus of my research program has been the role of nitric oxide in heart failure post-MI. When nitric oxide was discovered in the vascular endothelium about 30 years ago, it was considered solely as a vasodilator that relaxes the vascular smooth muscle. We now know that nitric oxide is also a signaling molecule that regulates functions of almost every organ during health and disease. An important contribution from my lab is the demonstration that myocardial inducible nitric oxide synthase (iNOS) expression is increased after MI and increased iNOS expression plays an important role in the development of heart failure post-MI. Our study showed for the first time that iNOS may represent a therapeutic target for the treatment of heart failure post-MI. In addition, our recent studies demonstrated that neuronal nitric oxide synthase (nNOS) protects the heart from ventricular arrhythmia post-MI via regulation of several key Ca2+ handling proteins.
3. Maternal Diabetes and Congenital Heart Defects
Diabetes is a major health problem worldwide. Women with pre-existing diabetes (type 1 or 2) have 3-5 times higher risk of developing congenital heart defects in their offspring. We have recently demonstrated that pregestational diabetes induced by streptozotocin (STZ) in mice leads to congenital heart defects including atrial and septal defects, tetralogy of Fallot, transposition of great arteries, double outlet right ventricle and hypoplastic coronary arteries in the offspring, which simulates diabetes-induced congenital heart defects in humans. Notably, treatment with N-acetylcysteine (NAC) in the diabetic mothers inhibits oxidative stress and prevents the development of congenital heart defects in the offspring. Our ongoing research is to investigate how maternal diabetes affects heart health in the offspring and its underlying molecular mechanisms in mice. Our studies may have implications in the treatment of women with maternal diabetes to prevent adverse cardiac outcomes in the offspring.
4. Epicardial Activation and Cardiac Repair
The epicardium is an outside layer of epithelial cells that cover the heart. Its major function in the adult is to reduce friction between the heart and pericardial membrane during heart contractions. Notably, during embryonic heart development, the epicardium contributes to the formation of coronary arteries and growth of heart muscle. In the adult heart, the epicardium can be activated after myocardial infarction (MI). We recently demonstrated that cardiac-specific overexpression of stem cell factor (SCF) improves cardiac function and animal survival post-MI. We further showed that cardiac specific SCF overexpression promotes epicardial activation and myocardial arteriogenesis post-MI. Ongoing studies are investigating molecular mechanisms of epicardial activation and strategies to enhance the regenerative potential of the adult epicardium post-MI.
5. Signal Transduction and Cardiac dysfunction in Sepsis
Another area of my research is the signal transduction mechanisms that lead to inflammatory cytokine expression and cardiac dysfunction during sepsis. Our work is focused on tumor necrosis factor-alpha (TNF-α) in the heart as TNF-α is considered a major cytokine that causes cardiac depression during sepsis. We demonstrated that eNOS promotes while nNOS inhibits TNF-α expression in the heart during sepsis. We showed for the first time an important role of Nox2-containing NADPH oxidase in cytokine expression and cardiac dysfunction during sepsis. Genetic deletion of Nox2 or pharmacological inhibition of NADPH oxidase activity decreases myocardial TNF-α expression and improves cardiac function during sepsis. In addition, we demonstrated an important cross-talk between MAPKs in sepsis. Specifically, we showed that JNK1/c-fos inhibits ERK1/2 and p38 MAPK signalling, leading to decreased cardiomyocyte TNF-α expression and improvements in cardiac function during sepsis. These studies have provided novel insights into the pathogenesis of cardiac dysfunction during sepsis. Furthermore, our studies suggest that modulation of different NOS isoforms and inhibition of Nox2-containing NADPH oxidase may serve as potential strategies for the treatment of sepsis.