Cocktail Therapy Combining SGLT2 Inhibitor, Entresto, and Adipose-Derived Mesenchymal Stem Cells Prevents Abdominal Aortic Aneurysmal Complication Syndrome in Rodents

Background: This study investigated whether triple combination therapy [dapagliflozin (DAPA) + sacubitril/valsartan (Entresto) + adipose-derived mesenchymal stem cells (ADMSCs)] offered additional benefits on preventing complication syndrome [defined as abdominal aortic aneurysm (AAA) dilatation, muscle layer destruction and inflammation] in rodents with AAA. Methods: Adult male Sprague-Dawley rats (n = 54) were equally categorized into group 1 (sham control), group 2 (AAA only), group 3 [AAA + DAPA (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 × 106 cells) by intravenous administration from day 7 after AAA induction for 3 consecutive dosages at 3-day intervals)], and group 6 (AAA + combined DAPA-Entresto-ADMSCs). Results: The results showed that the AAA diameter at day 28 was smallest in group 1, biggest in group 2, significantly larger in group 4 than in groups 3/5/6, and significantly larger in groups 4/5 than in group 6; however, there was no difference between groups 4 and 5 (all p < 0.0001). Light microscopic findings demonstrated that the AAA intimal thickness (i.e., indicator of intimal hyperplasia)/fibrotic area/number of immune-inflammatory [cluster of differentiation (CD) 3+/CD4+/matrix metalloproteinase [MMP] 2+/MMP9+] cells displayed an identical pattern, whereas the integrity of the 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 (tumor necrosis factor-alpha/interleukin (IL)-1 beta/IL-6/MMP2/ MMP9)/fibrosis (transforming growth factor-beta/ mothers against decapentaplegic homolog 3) markers displayed an identical pattern, whereas the protein expressions of tissue inhibitors of metalloproteinases (tissue inhibitor of metalloproteinases-1/tissue inhibitor of metalloproteinases-2) and apoptosis (cleaved-Caspase3/cleaved-poly(ADP-ribose) polymerase) 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 an innovative therapeutic modality for AAA.