Novel Beneficial Cardiovascular Effects of Natural Activators of Autophagy.

Autophagy is an intracellular process that is in charge for the degradation of senescent or dysfunctional cellular components through their sequestration by vesicles called autophagosomes and their subsequent degradation in lysosomes. The primary molecules derived from this catabolic process are finally recycled and reused for other cellular purposes. Autophagy is a paramount process for the regulation of cellular homeostasis particularly in response to stress. Activation of autophagy limits myocardial damage induced by ischemia, chronic myocardial infarction, mechanical stress, and heart failure. Autophagy also attenuates vascular damage and lessens atherosclerosis development. In the past few years, several natural compounds have gained momentum because of their ability to exert beneficial cardiovascular effects and to activate autophagy. Trehalose is a nonreducing sugar made of 2 molecules of glucose joined by means of an α-1,1 glycosidic linkage. It is a natural disaccharide synthetized by diverse life beings, such as yeasts, tardigrades, worms, insects, and vegetables, particularly during stress. On the contrary, trehalose cannot be synthetized by mammals, including humans, because of the lack of biosynthesis genes. The scientific attention to this sugar raised over the years because trehalose synthesis increases life span in lower organisms and protects them against injury caused by desiccation, extreme temperatures, reactive oxygen species, and misfolded protein accumulation. Exogenous administration of trehalose was also shown to protect mammalian cells in response to stress. Interestingly, Sarkar et al demonstrated that trehalose has a great ability to increase autophagy independently of mTOR (mammalian target of rapamycin) signaling. Trehalose is also potentially able to treat human disease. Oral administration of this disaccharide is able to dramatically reduce the development and progression of neurodegenerative disorders, hepatic steatosis, kidney injury, insulin resistance, and pancreatitis, mostly through the stimulation of autophagy. Ingested trehalose is metabolized by intestinal trehalase enzyme, which breaks down the disaccharide into 2 glucose molecules. However, a certain amount of trehalose is still able to pass the gut barrier and to accumulate in peripheral organs after oral intake, thereby exerting direct beneficial effects. Trehalose is also able to exert beneficial effects in the cardiovascular system. Trehalose reduced cardiomyocyte death in response to energy stress in cardiomyocytes in vitro. Oral administration of trehalose significantly reduced cardiac remodeling, dysfunction, and heart failure in a mouse model of chronic myocardial infarction through the activation of autophagy. In fact, trehalose administration significantly activated autophagy and mitophagy in cardiomyocytes, and its beneficial cardiac effects were blunted in Beclin-1 mice, which display genetic inhibition of autophagy. Interestingly, Sergin et al recently showed that trehalose administration is also able to reduce atherosclerosis development in ApoE (apolipoprotein E) mice fed with high-fat diet. Trehalose administration activated autophagy in macrophages of these mice thereby reducing cytokine production and vascular inflammation. These beneficial effects were abrogated by macrophage-specific conditional deletion of Atg5 gene, indicating that activation of autophagy in these cells is required for trehalose antiatherosclerotic effects. Trehalose seems to exert beneficial cardiovascular effects also in human subjects. A recent clinical trial demonstrated that oral administration of this disaccharide reduced arterial aging in healthy middle-aged subjects. Mechanistically, trehalose seems to stimulate autophagy through the activation of TFEB (transcription factor EB). Trehalose activated TFEB in cardiomyocytes, and knockdown of this transcription factor attenuated the proautophagic effects of this disaccharide. Similarly, the antiatherosclerotic effects of trehalose were associated with TFEB activation. Future studies are required to evaluate how trehalose promotes TFEB nuclear localization and activation. Another natural activator of autophagy is spermidine. Spermidine is a polyamine usually found in mammals, including human subjects, in both circulating blood and tissues. It is found in different kinds of food, particularly wheat germ, natto, soy beans, and mushrooms. However, spermidine content in mammals is also determined by its synthesis rate and catabolism. Spermidine regulates cellular homeostasis and response to stress, by exerting antioxidant and anti-inflammatory functions and by regulating DNA stability, cellular growth, and survival. In addition, spermidine promotes protein deacetylation, thereby controlling multiple cellular processes. Spermidine is also a potent activator of autophagy, mostly through the inhibition The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (G.F., S.S.); Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli (IS), Italy (G.F., C.V., S.S.); and University of Salerno, Medicine and Surgery, Baronissi, Italy (C.V.). Correspondence to Sebastiano Sciarretta, MD, PhD, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 74, 04100 Latina, Italy. Email sebastiano. sciarretta@uniroma1.it Viewpoints