Impact of autophagy activation on cardiac remodeling and vascular damage: a translational study

Autophagy is a mechanism of intracellular degradation of senescent or damaged proteins and organelles that are sequestered by vesicles with a double lipid membrane, called autophagosomes, which then merge with lysosomes to degrade their contents. Experimental studies on animal models showed that activation of autophagy reduces cardiovascular damage in response to acute myocardial ischemia, pressure overload and chronic ischemic remodeling. In addition, autophagy is progressively inhibited by diabetes, which is frequently intertwined with atherosclerosis and cardiovascular diseases. Such diabetes-induced dysregulation of autophagy makes these conditions more vulnerable to stress. However, it is not clear whether autophagy defects are associated with increased vascular damage and endothelial dysfunction induced by metabolic derangements. It is also unknown whether a dysregulation of autophagy is associated with the presence of cardiovascular diseases in human subjects.
Recent work suggested that trehalose may be a suitable compound to activate autophagy in the setting of cardiovascular disorders. Trehalose is a natural, non-reducing α-linked disaccharide composed of two molecules of glucose that is synthesized by lower organisms, such as yeasts, bacteria, insects and plants, but not by mammals. Trehalose was shown to protect cells in response to different kinds of stresses through the activation of autophagy. Trehalose administration appears to be beneficial also for the treatment of cardiovascular diseases. It was recently demonstrated that trehalose administration activates autophagy in macrophages, thereby reducing vascular inflammation, and plaque extension. Our recent work also demonstrated that trehalose significantly reduces cardiac remodeling, dysfunction and heart failure in a mouse model of chronic myocardial infarction through the activation of autophagy. However, there are no data on the effect of trehalose administration on endothelial dysfunction and cardiac remodeling in human subjects. Therefore, the hypotheses and specific aims of our research proposal are:

Hypothesis 1: Activation of mitochondrial autophagy attenuates metabolic syndrome-induced endothelial dysfunction and chronic ischemic remodeling.
Specific Aim 1: We will test whether: 1) trehalose attenuates high fat diet-induced endothelial dysfunction and mitochondrial abnormalities in mice through the promotion of mitochondrial autophagy; 2) selective pharmacological activation of mitochondrial autophagy by Tat-Beclin1 reduces mitochondrial and endothelial dysfunction induced by high fat diet; 3) trehalose activates mitophagy in the heart and reduces chronic ischemic remodeling through TFEB-dependent activation of mitochondrial autophagy.

Hypothesis 2: Autophagy is impaired in circulating mononuclear cells of patients with coronary artery disease. Autophagy dysregulation in these cells is correlated with the extent of coronary artery atherosclerosis.
Specific Aim 2: We will test whether: 1) autophagy impairment in circulating mononuclear cells is associated with the presence of coronary artery disease in human subjects; 2) a dysregulation of autophagy in circulating mononuclear cells is associated with the extent of coronary artery disease and endothelial progenitor cell number (EPC); 3) autophagy activation by trehalose improves survival and functional capacities of EPC-derived endothelial cells.

Hypothesis 3: Oral trehalose administration in patients with coronary artery disease after acute myocardial infarction prevents chronic cardiac remodeling.
Specific Aim 3: We will test whether chronic oral administration of trehalose for 6 months in patients with acute ST-elevation myocardial infarction (STEMI): 1) reduces left ventricular end-diastolic volume index (LVEDVi) as assessed by cardiac MRI (primary endpoint); 2) improves left ventricular ejection fraction and reduces left ventricular fibrosis and mass (secondary imaging endpoints); 3) reduces the risk for major adverse cardiovascular events (secondary clinical endpoints).

Hypothesis 4: Oral trehalose administration in patients with coronary artery disease after STEMI improves endothelial function, increases endothelial progenitor cells number and reduces inflammation and oxidative stress.
Specific Aim 4: We will test whether chronic oral administration of trehalose in patients who presented with acute STEMI: 1) increases endothelial function; 2) promotes autophagy in circulating mononuclear cells and increases the number of endothelial progenitor cell; 3) reduces circulating levels of markers of inflammation and oxidative stress.