The role of vascular smooth muscle in AAA pathogenesis and targets for SGLT2i intervention. IL-17A induces migration and proliferation of primary human aortic VSMCs through TRAF3IP2-dependent ROS generation, NLRP3 expression, caspase-1 activation, and proinflammatory and promitogenic IL-1b and IL-18 expression. Besides, ALDH-2 is a detoxifying enzyme for toxic aldehydes, and deficiency of ALDH2 increases the accumulation of toxic aldehydes and increases ROS by disrupting antioxidant defences, which in turn further inhibits ALDH2 and promotes VSMCs phenotypic conversion and apoptosis; SGLT2i treatment significantly improved ALDH2 activity and inhibited these changes. SGLT2 inhibitors exert antimigratory and antiproliferative effects through antioxidant and anti-inflammatory.SGLT2 inhibitors stimulate HO-1 expression in VSMCs by the ROS-Nrf2 pathway; HO-1 degrades heme to equal amounts of CO and bilirubin and inhibits proliferation and migration of VSMCs. SGLT2i directly inhibits VSMCs phenotypic transformation probably through inhibition of NHE1. VSMCs: vascular smooth muscle cells; IL: interleukin; TRAF3IP2: tumor necrosis factor receptor-associated factor interacting protein 2; NLRP3: nucleotide-binding domain and leucinerich repeat containing family pyrin domain containing 3; HO-1: heme oxygenase-1; Nrf2:NF-E2-related factor-2.

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... Ang-II infusion, AAA lesion size, and lesion inflammatory cell accumulation, 53 and some studies have demonstrated that the inhibition of NHE-1 can prevent VSMCs proliferation. 54 Taken together, SGLT2i may inhibit the development of AAA by suppressing the production of proinflammatory factors and inhibiting the phenotypic transformation of VSMCs (Fig. 2). The role of endothelium in AAA pathogenesis and endothelium targets of SGLT2i intervention. In response to exogenous antigens and hemodynamics, NOX and xanthine oxidase activities are activated, leading to the accumulation of cytosolic H + and lactate. As a result, the cytosolic pH decreases, leading to acidosis. To compensate for the ...

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... enzyme for nitroglycerin and inactivating enzyme for reactive aldehydes removal, which has a great impact on the development of endothelial dysfunction 64,65 (Fig. 1). Moreover, ALDH2 deficiency increases the susceptibility of Ang IIinduced AAA formation by disrupting antioxidant defense, increasing VSMC phenotypical switch/apoptosis (Fig. 2), and vascular inflammation. EMPA treatment has been reported to improve cardiac function and exercise tolerance in ALDH2 * 2 (A single point mutation at E487K of ALDH2 known as ALDH2 * 2 intrinsically lowers ALDH2 activity) mutant diabetic mice by reducing 4-hydroxy-2-nonenal protein adherences in cardiac mitochondria. 66,67 SGLT2i ...