Researchers have found that red blood cells have an innate ability to trigger a pathway that protects the heart from injury during periods of low oxygen, such as during a heart attack. The effect was stronger in people fed a diet high in nitrates, found in green leafy vegetables like spinach and arugula.
Red blood cells (RBCs) carry oxygen from the lungs to the rest of the body, returning carbon dioxide to the lungs where it’s expelled. However, some studies have suggested that in addition to their role as oxygen carriers, RBCs can sense hypoxia, or low oxygen levels, and respond by producing a signal that causes the release of nitric oxide (NO), which causes vasodilation or widening of the blood vessels.
NO is a naturally produced vasodilator. It’s thought, somewhat controversially, that its actions produce an effect that protects the heart against injury during hypoxia. Now, researchers from the Karolinska Institutet in Sweden have investigated the RBC signaling pathway to determine whether the cells have an innate ability to induce cardioprotection when oxygen levels are low.
First, the researchers looked at whether RBCs exposed to hypoxia released a cardioprotective mediator. Introducing RBCs from mice exposed to normal and low oxygen levels to mouse myocardial infarction (heart attack) models, they found that the hypoxic RBCs significantly improved heart function and reduced the size of tissue damage caused by low oxygen levels compared to RBCs exposed to normal oxygen levels.
Having determined that a cardioprotective factor was released from RBCs during hypoxia, the researchers set about determining the nature of this compound. They knew that RBCs carry soluble guanylate cyclase (sGC), which forms guanosine 3’,5’-cyclic monophosphate (cyclic GMP or cGMP), a messenger molecule that modulates many bodily pathways, including vasodilation. So, to determine the involvement of sGC, they exposed RBCs taken from mice that’d been genetically modified not to produce sGC to hypoxia and administered them to myocardial infarction models. The RBCs failed to protect the hearts against injury.
The next step was to determine if cGMP, the product of sGC, was exported from the RBCs and its role in the cardioprotective effect produced by hypoxic RBCs. Phosphodiesterase 5 (PDE5), a cGMP inhibitor, was administered to the hypoxic RBCs before they were introduced to the heart model. The researchers found that the introduction of PDE5 abolished the cardioprotective effect.
Since they’d confirmed that the sGC-cGMP pathway played a role in RBC-induced cardioprotection, the researchers looked at NO’s role in the pathway. In the body, inorganic nitrate can be reduced to nitrite and further reduced by deoxygenated hemoglobin to NO. So, they put inorganic nitrate in the mice’s drinking water for four weeks, after which they collected RBCs and administered them to the heart models. Hearts receiving hypoxic RBCs from nitrate-treated mice showed significantly better recovery and smaller tissue damage size than those from control mice. The researchers found that the cardioprotective effect of nitrate and hypoxia was greater than that of hypoxia alone.
To translate the beneficial effect of adding nitrate in mice to the clinical situation, the researchers collected RBCs from three groups of human subjects who’d been randomized to a five-week dietary intervention: two groups with high nitrate intake in the form of a potassium nitrate tablet or nitrate-rich vegetables, and one group receiving a low dietary intake of nitrate. These RBCs were then administered to rat heart models subjected to hypoxia. RBCs from both high-nitrate groups significantly improved cardiac recovery compared with those from the low-nitrate group.
“The results show both that the red blood cells convey protection against injury in the heart in the event of low oxygen levels, and how that protection can be enhanced through simple dietary advice,” said Jiangning Yang, the study’s lead author. “This may be of great importance for patients at risk of myocardial infarction.”
The researchers plan to develop drugs that activate the RBC’s protective signaling mechanism during hypoxia.
“In addition, we need to map how the blood cells transmit their protective signal to the heart muscle cells,” said John Pernow, a corresponding author of the study.
The study was published in the Journal of Clinical Investigation.
Source: Karolinska Institutet