Oxidative stress has long been linked with various disease states, from atherosclerosis to heart failure (HF) to neurodegeneration.
In 2018, researchers at Brigham and Women’s Hospital used a “chemogenetic approach” to show that oxidative stress has a causal role in HF in a paper published in Nature Communications. Researchers in the lab of Thomas Michel, MD, PhD, at the Brigham used a chemogenetic approach to express D-amino acid oxidase (DAAO), a yeast enzyme, in cardiac myocytes. When the animals received the amino acid D-alanine in their drinking water, intracellular hydrogen peroxide was generated by the DAAO enzyme in heart tissues, leading to oxidative stress and causing heart failure. Drugs used to treat heart failure in patients also reversed the heart dysfunction in this animal model, which Dr. Michel and colleagues described in the American Journal of Physiology–Heart and Circulatory Physiology.
More recently, the researchers used their approach to generate oxidative stress in the vascular endothelium, planning to explore diseases such as hypertension and aortic aneurysms. Surprisingly, the transgenic mice developed neurodegeneration, mitochondrial dysfunction, and cardiac hypertrophy caused by neurovascular oxidative stress.
Dr. Michel, a senior physician in the Division of Cardiovascular Medicine at the Brigham and a professor of Medicine at Harvard Medical School, and Shambhu Yadav, PhD, a research fellow in the Division, and colleagues describe the unexpected findings in a recent publication in Nature Communications.
The team generated transgenic mice that expressed DAAO under the control of the Cdh5 promoter, thought to be specific to endothelial cells. But when adult DAAO-TGCdh5 mice were provided with D-alanine, they rapidly developed marked sensory ataxia. Further investigation showed that the DAAO transgene was being expressed in sensory neurons, and the ataxia in these mice was being caused by oxidative stress and mitochondrial dysfunction in neurons within dorsal root ganglia (DRG) and nodose ganglia innervating the heart. The DRG contains the neuronal cell bodies that send axons to the dorsal spinal cord tracts. The mice became incapacitated within days to a few weeks after starting D-alanine feeding, but co-administration of oral antioxidants attenuated the ataxia.
Adult DAAO-TGCdh5 mice also developed cardiac hypertrophy after chronic chemogenetic oxidative stress, but there was no evidence of transgene expression in cardiac muscle cells (cardiac myocytes). To investigate further, the researchers generated mice in which the DAAO transgene was expressed in blood vessels but not DRG neurons. When these mice received D-alanine, no ataxia developed, and the mice did not develop any cardiac abnormalities. These findings suggest that the neuronal expression of DAAO explains both the ataxia and cardiac hypertrophy observed in DAAO-TGCdh5 mice.
The combination of sensory ataxia, DRG degeneration, mitochondrial dysfunction, and cardiac hypertrophy observed in DAAO-TGCdh5 mice is similar to the signs and symptoms of Friedreich’s ataxia, the most common form of inherited ataxia in humans. Friedreich’s Ataxia is a progressive neurodegenerative disease, but death in patients is most commonly a consequence of cardiac disease. The transgenic/chemogenetic approach used by Dr. Michel’s lab has identified important connections between peripheral sensory nerves and cardiac remodeling. Additional studies of DAAO-TGCdh5 mice might show whether degeneration of sensory neuronal ganglia due to neuronal oxidative stress has a pathophysiological role in the cardiac remodeling associated with neurodegenerative disease states.