Induction of Autophagy Slows High Fat Diet Induced Atherosclerosis in Mice
Atherosclerosis is the name given to the growth of fatty lesions in blood vessel walls, narrowing and weakening blood vessels, and eventually rupturing to cause a heart attack or stroke. This is the primary cause of human mortality. Many approaches have been demonstrated to slow the progression of atherosclerosis in the most commonly used mouse models, in which atherosclerosis is rapidly induced by a combination of high fat diet and the disabling of genes, such as APOE and LDLR, that are important to maintain normal blood cholesterol levels and cholesterol transport. Very few approaches have been shown to produce a reduction in the size of atherosclerotic lesions once they are established, however.
In today's open access paper, researchers demonstrate that a small molecule capable of provoking increased autophagy in a number of cell types relevant to atherosclerosis can meaningfully slow development of lesions in APOE-knockout mice. This is reasonable. Dysfunction in both (a) the endothelial cells lining blood vessels and (b) the macrophages responsible for clearing cholesterol from blood vessel walls is important in atherosclerosis. Increased operation of autophagy tends to help cells resist stresses that would otherwise disable them, kill them, or change their behavior for the worse, such as by inducing a senescent state. It should be expected to adjust the tipping points for formation and growth of atherosclerotic lesions. It most likely won't do anything to reverse existing lesions, however. Few approaches can, and if upregulation of autophagy was one of them, then exercise would be able to modestly reverse established atherosclerosis - which is not the case.
In the past, we showed that autophagy inducers can prevent or mitigate cardiovascular diseases, including myocardium infarction and heart failure. Due to their galenic properties and reduced cost, small molecules are particularly interesting for the prevention or treatment of cardiovascular diseases. Thus, high nutritional spermidine uptake is associated with reduced cardiovascular morbidity and mortality in humans and spermidine supplementation reduces the severity of atherosclerosis in mice. Spermidine acts against normal cardiac aging, as well as against high-salt diet-induced cardiac insufficiency. The copper-chelating agent triethylenetetramine (TETA) improves cardiovascular function and can induce the regression of pressure overload-induced cardiac hypertrophy. Another autophagy inducer, 4,4'-dimethoxychalcone (4,4'-DC) prevents myocardial necrosis after ligation of the left coronary artery. Furthermore, another, structurally related chalcone, 3,4-dimethoxychalcone (3,4-DC), prevents myocardial necrosis and induces autophagy in multiple mouse organs.
Atherosclerosis is the most prevalent aging-associated cardiovascular disease, providing the pathogenic substratum of most cases of myocardial infarction, stroke, aortic aneurysm, and arterial occlusion affecting internal organs or the femoral artery. The etiology of atherosclerosis appears complex but involves an important dysfunction of innate and cognate immune effectors, with macrophage-mediated inflammatory responses and the formation of foam cells (macrophages exhibiting the accumulation of lipid droplets in their cytoplasm) as prominent elements of the disease process. Given the anti-inflammatory effects of autophagy and the important anti-atherosclerotic role of lipophagy (a subtype of autophagy causing the removal of lipid droplets), we wondered whether the administration of pharmacological autophagy inducers might protect against the development of atherosclerosis.
Based on these premises, we attempted to identify the best strategy to prevent atherosclerosis by searching for agents among the aforementioned compounds that would induce autophagy in all cardiovascular disease-relevant cell types, i.e., cardiomyocytes, endothelial cells, and macrophages. As we report here, 3,4-DC stood out as a broad autophagy inducer. In a series of in vivo experiments involving two distinct mouse models of atherosclerosis, we obtained preclinical evidence indicating that 3,4-DC can efficiently slow the onset of this condition.