Surprising protector of heart health identified

The powerhouse of the cell could be a “potent target” for therapies to mitigate or correct heart failure, according to a new study by a team of researchers based in Japan. In a study in mice and a cell line of human heart cells, they found that the molecular marker that typically signals cellular damage may actually play a protective role in the heart, especially during a heart failure.
They published their results, which identify a protein modification that protects heart tissue in low oxygen circumstances, like after a heart attack, on Jan. 2 in Nature Communications.

“The primary role of myocardial mitochondria is to sustain high energy production while maintaining intracellular redox balance,” said first author Akiyuki Nishimura, project associate professor in the Division of Cardiocirculatory Signaling at the National Institute for Physiological Sciences (NIPS), one of the National Institutes of Natural Sciences (NINS), in Japan. “Oxidative stress due to the accumulation of reactive oxygen species (ROS) and ROS-derived electrophiles is believed to exacerbate the prognosis of ischemic, or low-oxygen, heart diseases.
Mitochondria typically power the cell and help maintain homeostasis by balancing life-sustaining — and potentially ending — oxidation-reduction (redox) reactions. These involve transferring electrons, with the oxidized molecule losing electrons and the reduced one gaining electrons. An imbalance in this exchange can increase oxidative stress, which can lead to cellular damage.
“Oxidative stress caused by increased reactive oxygen species production is a key feature of ischemic heart disease and is believed to be involved in the development and progression of heart failure,” Nishimura said. “Therefore, several clinical studies targeting oxidative stress have been performed to improve the outcome of heart failure patients but most of them have failed.”
Rates of oxidative stress are indicated by levels of GSSG, the oxidized form of glutathione (GSH), an antioxidant that helps the body repair damage. In health, there should be much more GSH than GSSG. The lower the ratio between the two molecules — the more GSSG — the more likely there is lasting oxidative damage in the body. However, Nishimura said, specific studies to investigate if the obvious answer of increasing GSH would improve outcomes have failed.

In this study, the researchers analyzed whether GSSG might be the solution. They found that after heart damage caused by low-oxygen, GSSG modified a sulfur-containing amino acid on a protein called Drp1, protecting mitochondrial function. This protects the heart, the researchers said, because mitochondria can become dysregulated and cause further damage — including heart failure — without enough oxygen.
“These findings prove the breakthrough therapeutic potential of GSSG for ischemic chronic heart failure,” Nishimura said, noting that the team next plans to investigate whether sulfur-based redox reactions have principal roles in disease progression in other organ systems beyond the cardiovascular system.

Other authors on the paper are Xiaokang Tang, Makoto Sanbo, Masumi Hirabayashi, Kenta Kobayashi and Motohiro Nishida, all with NIPS; Seiryo Ogata and Takaaki Akaike, Graduate School of Medicine, Tohoku University; Kowit Hengphasatporn and Yasuteru Shigeta, Center for Computational Sciences, University of Tsukuba; Keitaro Umezawa, Tokyo Metropolitan Institute for Geriatrics and Gerontology; Yuri Kato, Yoshito Kumagai and Nishida, Graduate School of Pharmaceutical Sciences, Kyushu University; Yuko Ibuki, Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka; Yasunari Kanda, Division of Pharmacology, National Institute of Health Sciences; and Yasuteru Urano, Graduate School of Pharmaceutical Sciences and Graduate School of Medicine, The University of Tokyo. Nishimura, Tang and Nishida are also affiliated with NINS’ Exploratory Research Center on Life and Living Systems and SOKENDAI (The Graduate University for Advanced Studies).