Publication Date
2025
Document Type
Thesis
Committee Members
Khalid M. Elased, Pharm.D., Ph.D. (Advisor); Mauricio Difulvio, Ph.D. (Committee Member); Courtney Sulentic, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Type 2 diabetes significantly increases the risk of diabetic cardiomyopathy (DCM) and nephropathy, largely due to hyperglycemia-induced activation of the renin-angiotensin system (RAS) and elevated levels of angiotensin II (Ang II). Angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) mitigate the deleterious effects of Ang II by generating Ang-(1-7), a cardioprotective vasodilator. ACE2 is essential for cardiac function, while its deficiency exacerbates dysfunction. Furthermore, the silent information regulator 1 (SIRTl) promotes ACE2 expression and contributes to cardiovascular protection. Despite the availability of several classes of antidiabetic medications, some cardiovascular complications of diabetes persist, and intensive glycemic control does not always improve cardiovascular outcomes and may pose risks. Furthermore, certain antidiabetic drugs, such as rosiglitazone (a PPAR-γ agonist), have been linked to adverse cardiovascular effects, including heart failure and myocardial infarction. In contrast, pioglitazone, another PPAR-γ agonist, has demonstrated cardioprotective benefits in clinical trials, improving insulin sensitivity while reducing cardiovascular risk. These findings underscore the need for therapies that modulate specific targets such as RAS and lowering glycemia alone is not enough to reduce the cardiovascular complications of diabetes. Canagliflozin, a sodium glucose co-dtransporter 2 (SGLT2) inhibitor is approved for heart failure. This study investigated the effects of pioglitazone and canagliflozin on cardiac ACE, ACE2, NEP, SIRT1, a disintegrin metalloprotease 17 (ADAM17), neutrophil gelatinase associated lipocalin (NGAL), and kidney injury molecule-I (KIM-I) in db/db mice. Both pioglitazone and canagliflozin treatments significantly lowered blood glucose. Cardiac ACE2 was detected as full-length (l00 kDa) and fragmented (37 kDa) bands, with increased expression at 37kDa in db/db mice. Both pioglitazone and canagliflozin treatment significantly increased cardiac ACE2 expression and activity, suggesting cardioprotective effects. While cardiac NEP expression was reduced in db/db and further downregulated by pioglitazone, canagliflozin had no significant effect. Elevated ADAM I7 expression in db/db mice may contribute to ACE2 and NEP enzymatic fragmentation. Cardiac SIRTI expression, was decreased in db/db mice, was increased by pioglitazone treatment. Both treatments reduced cardiac NGAL, while only pioglitazone lowered cardiac KIM-I. In conclusion, both drugs enhance cardiac ACE2 and reduce cardiac NGAL levels, potentially protect against DCM. However, pioglitazone has a multi-target cardioprotective mechanism, further downregulates cardiac KIM I and NEP while upregulating SIRTI, indicating a distinct cardioprotective mechanism that complements their glucose-lowering effects.
Page Count
114
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2025
Copyright
Copyright 2025, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0001-5541-2473
