It has been recently demonstrated that cigarette mainstream smoke could enhance the proteolytic activity of MMPs including MMP-2 and -9 induced by Ang II and accelerate both formation and severity of AAAs in the hypertensive apolipoprotein E-deficient mice, [26] while cigarette smoke extract significantly downregulated TIMP-3 in aortic endothelial cells [74]. Here, APOE is linked to achalasia-alacrima syndrome.