Mending Myocardial Infarctions With Mangos: Mangiferin Protects Mice From Heart Attacks By Preventing Heart Cell Loss
Heart attacks, known as myocardial infarctions, are one of the most prevalent causes of morbidity and mortality worldwide. But the prognosis remains poor, in part because the adult heart has little, if any, regenerative potential. So, preventing heart cell loss could be an efficient way to treat heart attacks and promote recovery.
Mangiferin, derived from mango fruits and their by-products, is recognized as a safe natural product and has several beneficial effects, including the prevention of programmed cell death (apoptosis). Recent studies also suggest that mangiferin has anti-apoptotic activity in myocardial injury, but how mangiferin works to protect the heart from myocardial infarction remains unclear.
In the present study, Chen and colleagues showed that mangiferin prevents heart cell loss by inhibiting apoptosis after myocardial infarction through the activation of longevity-associated proteins in heart cells. “These data help us to better understand the role and detailed mechanism of mangiferin in myocardial infarction, and suggest that mangiferin may have an interesting potential in following studies towards clinical evaluation,” concluded the authors.
Apoptosis is Apropos for Heart Attacks
Apoptosis contributes to the progression of many diseases and leads to organ dysfunction. During heart attacks, apoptosis of cardiomyocytes — the main contractile muscle cell in hearts — is the main cause of heart cell loss and plays a critical role in subsequent heart failure. So, finding a safe and effective anti-apoptotic therapeutic strategy for myocardial infarction is important and may greatly improve the prognosis of patients.
For these reasons, Chen and colleagues targeted apoptotic cell death in myocardial infarction with the anti-apoptotic mangiferin to tease out whether and how the mango-derived compound preserved heart function and prevented the progression to heart failure in mice. The researchers did find that mangiferin significantly reduced cardiomyocyte apoptosis, which was accompanied by preservation of cardiac function and prevention of heart failure progression after myocardial infarction in mice.
Importantly, mangiferin’s effects appeared to be specific to cardiomyocytes and not other cell types that make up the heart. After myocardial infarction, mangiferin did not affect the apoptosis of interstitial cells, which contain a variety of cell types, such as immune cells and cells related to blood vessels called endothelial cells, smooth muscle cells, and pericytes. These cardiac interstitial cells are important players in organ injury response after myocardial infarction. They represent regulatory functions in tissue maintenance and repair, and apoptosis of these cells also plays a respective role in the heart’s breakdown following myocardial infarction. This demonstrated that mangiferin could not prevent cardiac interstitial cells from apoptosis in myocardial infarction, which means that mangiferin protects the heart against myocardial infarction mostly by preventing cardiomyocyte apoptosis.
Foxy Lady: Mangiferin Protects Against Heart Attacks Through Sirt1/FoxO3a
The researchers then went on to show that mangiferin alleviates myocardial infarction insult largely by up-regulating a protein in heart cells called Sirt1, which is involved in a wide variety of biological functions in multiple tissues and organs pertaining to cell health and viability. In the heart, Sirt1 is considered to be related to cell apoptosis, survival, growth, metabolism, and senescence — the permanent arrest in cell proliferation associated with aging. Mice with Sirt1 deleted specifically in their cardiomyocytes were not able to exert the preventative effects of mangiferin on heart attacks, indicating the essential role of Sirt1 in mangiferin-mediated protection from heart attacks.
Sirt1 exerts its function in part by modifying a large number of proteins through a process called deacetylation, which is the removal of a chemical structure called an acetyl group. Often these target proteins, such as the longevity-linked FoxO3a, are inhibited when they carry an acetyl group and become activated when SIRT1 deacetylates them. The results from this study show that mangiferin treatment down-regulates FoxO3a acetylation, and this effect is absent after Sirt1 knockout or silencing, indicating that mangiferin regulates FoxO3a deacetylation through Sirt1 activation after myocardial infarction. When they prevented FoxO3a deacetylation, the protective effects of mangiferin were abrogated. These results are in agreement with previous studies showing that FoxO3a‐dependent apoptosis plays a key role in cardiomyocyte apoptosis after heart attacks.
Sirt1 also acts as an epigenetic enzyme, meaning it activates and deactivates genes without any change in the underlying DNA sequence of the organism. This means that mangiferin may also be anti-apoptotic by exerting epigenetic effects. Several studies indicate that some functional food compounds have the potential for the treatment of cardiac diseases through their action on the epigenome like resveratrol (found in berries, grapes, and peanuts) and the soy-related genistein. These plant-based products can induce epigenetic activation of cell survival genes or inactivation of harmful genes elicited by myocardial infarction, which help to promote cardiomyocyte survival after injury. As a bioactive compound derived from mango fruits, mangiferin could be used as a basis to design novel dietary approaches against ischemic heart diseases, the action of which would be mediated through Sirt1 regulation of the epigenome.
“Our results indicate that mangiferin prevents cardiomyocyte apoptosis and the subsequent heart failure by activating the Sirt1/FoxO3a pathway in myocardial infarction, and suggest that mangiferin may have an interesting potential in following studies towards clinical evaluation,” concluded Chen and colleagues. “These data help us to better understand the role and detailed mechanism of mangiferin in myocardial infarction, and suggest that mangiferin may have an interesting potential in following studies towards clinical evaluation.”
Chen L, Li S, Zhu J, et al. Mangiferin prevents myocardial infarction-induced apoptosis and heart failure in mice by activating the Sirt1/FoxO3a pathway [published online ahead of print, 2021 Feb 1]. J Cell Mol Med. 2021;10.1111/jcmm.16329. doi:10.1111/jcmm.16329