Basic Science
Sirtuin-7 as a Novel Therapeutic Target in Vascular Smooth Muscle Cell Proliferation and Remodeling
2021 Volume 85 Issue 12 Pages 2241-2242
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2021 Volume 85 Issue 12 Pages 2241-2242
Due to a modern lifestyle, individuals are constantly exposed to various environmental stresses leading to excess calorie intake. These marked changes in lifestyle and stressed environmental conditions have called for development of new molecular mechanisms to cope with the fight against hunger. Chronic satiety has resulted in an increase in cases of metabolic syndrome worldwide, leading to an increase in cardiovascular diseases. One reason for this could be diet; for example, the traditional Japanese diet is high in salt and carbohydrates. One study reported that calorie restriction by approximately 30% resulted in a significant increase in the lifespan of the monkeys.1 That study highlights the beneficial effects of calorie restriction. One mechanism underlying this effect involves the group of proteins called sirtuins. Sirtuins are involved in many processes, including aging, metabolism, stress resistance, apoptosis, and inflammation.2 To date, 7 sirtuin family proteins (Sirt1–7) have been identified. Of these, Sirt1 has been extensively studied in the cardiovascular system and has been shown to have a protective effect against vascular dysfunction in diabetes.3 Recently, new therapeutic approaches involving sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their beneficial effects in patients with cardiovascular diseases.
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Large-scale clinical studies have demonstrated the cardiorenal protective effects of SGLT2 inhibitors. For example, the EMPA-REG outcome trial consisted of patients subjected to secondary prevention among patients who originally had arteriosclerosis disease.4 However, the subsequent CANVAS, DECLARE-TIMI58, and CREDENCE trials confirmed that the merger of arteriosclerosis was approximately half, and that SGLT2 inhibitors were effective in primary prevention.5–7 In the DAPA-HF trial, dapagliflozin was administered to patients with heart failure with reduced ejection fraction (HFrEF) to investigate its effects on worsening of heart failure and the death rate, with the results showing that dapagliflozin markedly decreased the heart failure rate, regardless of the presence or absence of diabetes.8 That trial also showed delay in the decline in the estimated glomerular filtration rate (eGFR) with or without diabetes. Similarly, the EMPEROR-Reduced study showed that empagliflozin was effective not only in patients with diabetes, but also in patients with non-diabetic heart failure.8 Both dapagliflozin and empagliflozin reduced the rate of death or heart failure and improved complex renal outcomes regardless of diabetes status. Therefore, it can be speculated that there is an underlying mechanism of action of SGLT2 inhibitors that may indirectly target the cardiovascular system.
SGLT2 inhibitors are a class of drugs used to treat diabetes by increasing the excretion of sugars into the urine. Unlike SGLT2 inhibitors, insulin and other antidiabetic drugs have no effect on the prognosis of cardiovascular diseases. The major difference between SGLT2 inhibitors and other classic antidiabetic therapeutic agents is that the former cause sugars to be excreted out of the body. Thus, SGLT2 inhibitors may have the same effect as calorie restriction as a result of the excretion of sugars in the urine. Recent evidence suggests that SGLT2 inhibitors may activate Sirt1 and increase the expression of genes associated with fasting.9 If the improvement in the prognosis of cardiovascular disease by SGLT2 inhibitors is due to indirect caloric restriction effects, it will also be easier to understand the mechanism underlying their wide range of beneficial effects. In fact, it has been shown that SGLT2 inhibitors may increase ketone body production and change energy metabolism in myocardial and renal tissues, as happens during fasting.10 In addition to glucose and fatty acids, ketone bodies also produce ATP in cells, and play a particularly important role as a source of ATP production during long-term fasting. Interestingly, ketone body concentrations are increased in the blood of patients administered SGLT2 inhibitors, and similar response is observed during fasting. Thus, ketone bodies are not only useful as an energy source under a morbid environment, but they also have multifaceted roles, such as transcriptional regulation of signaling molecules and histone deacetylases (HDACs). HDACs are enzymes important for histone modification that allow DNA to be tightly enveloped around histones. Mammals have 4 classes of HDACs, and the Sirt gene family belongs to the Class III HDACs. Of the sirtuins, Sirt1, localized in the cytoplasm and nucleus, has been most widely studied in the cardiovascular system and in heart failure. However, not much is known about Sirt7.
In this issue of the Journal, Kimura et al provide a strong evidence to suggest that Sirt7 plays an important role in the proliferation of vascular smooth muscle cells (VSMCs) and promotes neointimal formation after vascular injury.11 The results reported by Kimura et al shows that Sirt7 expression increases in the femoral arteries of wild-type mice after injury. Mice deficient in VSMC-specific Sirt7 showed attenuated neointimal formation following vascular injury in vivo. In addition, Sirt7-deficient VSMCs showed reduced proliferative capacity in vitro.11 Sirt7 deficiency was also associated with upregulation of the miRNA 290-295 family and transcriptional downregulation of CDK2, and Kimura et al confirmed that Sirt7 negatively regulates these miRNAs by interacting with CUL4B, and that deletion of Sirt7 increases their expression and inhibits CDK2 expression.11 Sirt7 in VSMCs was also found to be involved in the development of neointimal lesions in the femoral artery wire injury model.
Clinical SignificanceVSMC proliferation is the foundation of the development of vascular remodeling.12,13 Pulmonary artery VSMCs in patients with pulmonary artery hypertension show excessive activation of hypoxia-inducible factor-1α and cancer-like proliferation.14–18 As described in an excellent review by Matsushima et al,2 Sirt plays an important role in longevity, calorie restriction, and DNA damage, but is also involved in aging, fasting energy responses, stress tolerance, apoptosis, and inflammation. Sirt has also been shown to play a role in biosynthetic mitochondria and regulate the circadian clock.19 Thus, as demonstrated in a previous study,20 the molecules that affect Sirt7 may be beneficial not only for heart failure, but also for the treatment and prevention of various vascular diseases. The effectiveness of approaches to inhibit Sirt7 seems promising and should be explored further in future studies.
None declared.
