BIOSKETCH AND RESEARCH INTERESTS
Anupam Agarwal, MD, professor and director of the division of nephrology, is focused on investigation of the heme oxygenase-1 (HO-1) gene, an inducible gene upregulated as a protective mechanism in many disease states and in multiple organ systems. The main function of the HO-1 enzyme is in degradation of heme, a prooxidant molecule which is increased in response to tissue injury. One of the goals of Dr. Agarwal’s research is to bridge the gap between bench and bedside, by applying the knowledge gained from his basic science work to patients, thereby advancing the practice of medicine.
Mitochondria are the powerhouse of the cell helping generate ATP, the basic unit of health and life. In a disease state, mitochondrial health is a net result of mitochondrial damage and clearance (mitochondrial fission and mitophagy) and mitochondrial generation (mitochondrial fusion and biogenesis). In this work, published in JCI Insight, the authors demonstrate the pivotal role of HO-1 in preserving mitochondrial structure and function in the heart in a model of doxorubicin-induced heart failure.
Authors of the paper, “Heme Oxygenase-1 Regulates Mitochondrial Quality Control in the Heart,” are Agarwal and James George; and Travis D. Hull (MSTP graduate), Ravindra Boddu, Cornelia C. Tisher, Amie M. Traylor, Lingling Guo, Bindiya Patel, Reny Joseph and Sumanth D. Prabhu, all of the UAB Department of Medicine; and Hagir B. Suliman and Claude A. Piantadosi, Duke University School of Medicine.
Induction of HO-1 gene in disease states is an important protective mechanism from oxidative stress induced cellular and mitochondrial damage. Heme, a strong prooxidant molecule is released in response to cell death and tissue injury. HO-1 degrades heme to equimolar quantities of cytoprotective byproducts. The exact mechanisms of HO-1 cytoprotection and improvement in mitochondrial health remain unclear.
In this validated mice model of doxorubicin related dilated cardiomyopathy, HO-1 overexpression prevented doxorubicin induced cardiac toxicity. Doxorubicin prevents a) mitochondrial biogenesis by inhibition of mitochondrial transcription factor A (TFAM), which is needed for replication of mitochondrial DNA and b) enhances mitochondrial fission by upregulating the fission mediators. These effects are inhibited by overexpression of HO-1.
The findings suggest an important role of HO-1 in cardiac protection from doxorubicin and other chemotherapeutic agents, and strongly imply development of treatments targeted at HO-1 gene for prevention of cardiac toxicity among patients receiving chemotherapeutic agents for management of cancer.