Sirtuins are a family of antiaging proteins that regulate cellular lifespan, metabolism, and resistance to stress. The potential protective effects of these sirtuin enzymes in age-related diseases, including cardiovascular diseases, are still being investigated intensively.
Now, a new preclinical study led by researchers from the University of South Florida Health (USF Health) has found that sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3) levels decrease and the ability to contract as the heart ages of the heart muscle cells (cardiomyocytes) interfere in response to ischemia-reperfusion injury (also known as reperfusion injury). Additionally, age-related SIRT1 and SIRT3 deficiency can affect heart function by altering mitochondrial dynamics, which play an important role in metabolic health and the inflammatory response, the researchers report.
The results were published online in Aging Cell on July 3.
“We have found that age-related changes in mitochondrial dynamics are caused by a SIRT1 / SIRT3 deficiency, particularly in the cardiomyocytes,” said study director Ji Li, PhD, professor of surgery at USF Health Morsani College of Medicine. “You need a strong presence of SIRT1 and SIRT3 to keep the mitochondrial dynamics in the heart healthy. Otherwise, the heart’s pumping function will be weak.”
Mitochondria produce the energy in living cells that is required for almost all processes. Heart muscle cells contain more mitochondria than any other cell because the heart needs a lot of energy to keep pumping blood around the body. Stable mitochondrial dynamics maintain a healthy balance between the constant division (splitting) and fusing (fusion) of mitochondria and help ensure the quality of these specialized structures known as the “powerhouse” of the cell.
Reperfusion, a common treatment after an acute heart attack, restores blood flow (and therefore oxygen) to an area of the heart that has been damaged by a blood clot blocking the coronary artery. Paradoxically, in some patients, this necessary revascularization procedure causes further injury to the heart muscle tissue surrounding the original myocardial infarction site. There are currently no effective therapies to prevent reperfusion damage.
To analyze the response of cardiac mitochondria to ischemic reperfusion stress, USF Health researchers erased SIRT1 or SIRT3 in cardiac muscle cells of mouse hearts and examined the mitochondrial response to ischemic stress due to restricted blood flow. The researchers found that the mitochondria in mouse hearts without cardiomyocyte SIRT3 were more prone to reperfusion stress than the mouse hearts with intact SIRT3. Cardiac mitochondrial dynamics (including shape, size, and structure of mitochondria) in these knockout mice were physiologically similar to those of aged (normal) wild-type mice that retained cardiac SIRT3.
In addition, the young mice with the SIRT1 or SIRT3 removed had measurably weaker cardiomyocyte contractions and showed age-like cardiac dysfunction when ischemia-reperfusion stress was introduced. In essence, the hearts of these otherwise healthy young mice without SIRT1 / SIRT3 looked and behaved like old hearts.
“We started this study to understand why older people are more likely to have heart attacks than younger people and why they are more likely to die even when they receive maximum treatment. Younger people are much more likely to recover from heart attacks and are less likely to have them.” of ischemia-reperfusion injury, “said Dr. Li, a member of the USF Health Heart Institute.” Our research suggests that one reason could be that both SIRT1 and SIRT3 are downregulated with age. Younger people have higher levels Amounts of these proteins that are needed to make mitochondrial dynamics healthier. “
The study also suggests that prior to surgical opening of blocked coronary arteries to restore blood flow in elderly patients, administering treatment to “rescue” (improve) their decreased SIRT1 / SIRT3 levels may increase tolerance to cardiac reperfusion stress, thereby reducing heart attack complications may and deaths, said Dr. Li. Such cardioprotective treatment could use a genetic approach to increase SIRT1 / SIRT3 production or an agonist (drug) to activate SIRT1 / SIRT3, he added.
If the results of her mouse model results can be transferred to human hearts, Dr. Li’s group is working with companies interested in developing and testing SIRT1 / SIRT3 activators to mitigate heart attack-related reperfusion damage.
“Our ultimate goal is to identify ideal targets for treating heart attacks, especially in the elderly,” said Dr. Li, whose research is supported by grants from the National Heart, Lung, and Blood Institute, the National Institute on Aging. and the National Institute of General Medical Sciences.