Abstract TH177: Cardiac RAS/SIRT1 Modulation by Pioglitazone and Canagliflozin Protects Against Diabetic Cardiomyopathy

Background: Type 2 diabetes increases the risk of diabetic cardiomyopathy (DCM), in part due to hyperglycemia-induced dysregulation of the renin-angiotensin system (RAS) and impaired cardioprotective signaling of ACE2/Ang-(1-7). Silent information regulator 1 (SIRT1) enhances ACE2 expression, while antidiabetic drugs such as pioglitazone (a PPAR-γ agonist) and canagliflozin (an SGLT2 inhibitor) can confer cardiovascular benefits beyond glycemic control. Despite effective glucose management with current therapies, diabetic complications persist, highlighting the need for targeted modulation of RAS. Hypothesis: We hypothesized that pioglitazone and canagliflozin would attenuate hyperglycemia and DCM in db / db mice by modulating the RAS and SIRT1 pathways, thus reducing cardiac fibrosis. Methods: Six-week-old male db/db and lean control mice received normal chow or chow supplemented with pioglitazone or canagliflozin (20 mg/kg/day) for 10–15 weeks. Cardiac expression of RAS components, SIRT1, ADAM17, was assessed by Western blot, enzymatic assays, and Masson’s trichrome staining. Glycemic control, ACE2 activity, and fibrosis markers were evaluated. Results: Both agents significantly reduced blood glucose in db / db mice (p < 0.001) but exhibited distinct cardiac effects. Western blot analysis revealed two cardiac ACE2 immunoreactive bands: a mature 100 kDa form and a 30 kDa fragment (kidney ACE2 appeared only as a full-length). Cardiac 30 kDa ACE2 expression was elevated in db / db mice (p < 0.001). Both treatments increased full-length ACE2 expression and activity, suggesting cardioprotection. Pioglitazone downregulated cardiac NEP and upregulated SIRT1 (p < 0.001), while canagliflozin had no effect on these targets. Masson’s trichrome staining confirmed attenuated cardiac fibrosis with both treatments. Data are presented as mean ± SEM for each group (n=5-8) Conclusion: Both Canagliflozin and pioglitazone enhance cardiac ACE2 expression/activity, implicating a protective role in DCM. Pioglitazone further downregulates cardiac NEP and upregulates SIRT1, indicating a distinct cardioprotective mechanism that complements their glucose-lowering effects. These findings advocate for therapies targeting RAS in diabetic cardiovascular complications.