Cocktail therapy of combined SGLT2 inhibitor, entresto and adipose-derived mesenchymal stem cells effectively prevents abdominal aortic aneurysmal associated complication syndrome in rodent

Abstract

Abstract Background This study tested that triple combination therapy [Dapagliflozin + Entresto + adipose-derived mesenchymal stem cells (ADMSCs)] offered additional benefits on preventing abdominal aortic aneurysm (AAA) against AAA complication syndrome (defined as AAA dilatation, muscle layer destruction and inflammation) in rodent. Methods and Results Adult-male SD rats (n = 54) were equally categorized into group 1 (sham control), group 2 (AAA only), group 3 [AAA + dapagliflozin (20 mg/kg/day orally from days 7 to 28 after AAA induction)], group 4 [AAA + entresto (100 mg/kg/day orally from days 7 to 28 after AAA induction)], group 5 [AAA + ADMSCs (1.0 x 106 cells) by intravenous administration since day 7 after AAA induction for 3 consecutive dosages at 3-day interval)] and group 6 (AAA + combined dapagliflozin-Entresto-ADMSCs). The result showed that the AAA diameter at day-28 was smallest in group 1, biggest in group 2, significantly increased in group 4 than in groups 3/5/6 and significantly increased in groups 4/5 than in group 6, but it showed no difference between groups 4/5 (all p < 0.0001). The light microscopic findings demonstrated that the AAA intimal thickness (i.e., indicator of intimal hyperplasia)/fibrotic area/numbers of immune-inflammatory (CD3+/CD4+/MMP2+/MMP9+) cells displayed an identical pattern, whereas the integrity of laminar structure of AAA medial-muscle layer/number of small vessels exhibited an opposite pattern of AAA diameter among the groups (all p < 0.0001). The protein expressions of inflammation (TNF-α/IL-1β/IL-6/MMP-2/MMP-9)/fibrosis (TGF-β/Smad3)/apoptosis (cleaved-Caspase3/cleaved-PARP) displayed an identical pattern, whereas the protein expressions of tissue inhibitors of metalloproteinases (TIMP1/TIMP2) displayed an opposite pattern of AAA diameter among the groups (all p < 0.0001). Conclusion The results of the present study support that triple therapy with DAPA + entresto + ADMSCs could be innovative therapeutic modality for AAA setting.