Thesis
The protective effect of alamandine on isoproterenol-induced cardiac dysfunction, remodeling, and immune responses in rat
University of Iowa
Master of Science (MS), University of Iowa
Spring 2024
DOI: 10.25820/etd.007483
Abstract
Background: Isoproterenol (ISO), a non-selective beta-adrenergic receptor agonist has been used as a pharmacological model to induce cardiac hypertrophy, fibrosis, and inflammation. Alamandine, a heptapeptide derived from angiotensin II, has been shown to exert antihypertensive and vasodilative actions and may represent a cardioprotective axis of the renin angiotensin system.
Objective: To assess the protective effect of alamandine on ISO-induced cardiac dysfunction, remodeling, and inflammation in rats.
Methods: Male Sprague Dawley rats received a two-week subcutaneous infusion of vehicle (saline), ISO (10 mg/kg/day) or a combination of ISO and alamandine (50 ng/kg/min). Cardiac function parameters were assessed by echocardiography, and gene expression (mRNA) of cardiac hypertrophy, fibrosis and inflammatory markers were assessed by RT-PCR. Histological staining was employed to assess cardiac morphological changes including hypertrophy and fibrosis. Immune cell characterization in heart and spleen tissue was done using flow-cytometry.
Results: Alamandine treatment for two weeks significantly reduced ISO-induced cardiac hypertrophy indicated by heart weight to body weight ratio. Echocardiographic assessment revealed that alamandine treatment significantly attenuated ISO-induced increase in left ventricular (LV) thickness and cardiac mass along with decrease in LV end diastolic volume and LV end systolic volume. Rats treated with alamandine had reduced E/E' ratio and increased E'/A' ratio indicating improved diastolic cardiac function. Prolonged isovolumetric relaxation time and isovolumetric contraction time and consequently higher myocardial performance index was observed in ISO alone group. Alamandine treatment significantly reduced these indicators. Histological analysis revealed that treatment with alamandine reduced ISO-induced increases in cardiomyocyte area and myocardial fibrosis area along with reduced mRNA expression of hypertrophy biomarkers - atrial natriuretic peptide, brain natriuretic peptide, beta myosin heavy chain (β MHC) and fibrosis genes – collagen-1, fibronectin, -smooth muscle actin. Flow cytometry analysis unveiled that alamandine treatment reduced neutrophil, CD8 T cells and M1 monocytes, but increased M2 monocytes deposition in LV, implying the reduction of inflammation in the heart. Moreover, treatment with alamandine reduced ISO-induced increases in mRNA expression of pro-inflammatory interleukin 6, monocyte chemoattractant protein-1 and CD 68 in LV. In addition, alamandine prevented ISO-induced increases in mRNA expression of angiotensin converting enzyme and angiotensin type 1 receptor in heart.
Conclusion: These data demonstrate that alamandine plays a cardioprotective role in improving cardiac function, hypertrophy, and fibrosis, probably via an immune mechanism to alleviate inflammatory responses during cardiac remodeling.
Details
- Title: Subtitle
- The protective effect of alamandine on isoproterenol-induced cardiac dysfunction, remodeling, and immune responses in rat
- Creators
- Nafis Md Irfan
- Contributors
- Shunguang Wei (Advisor)Jong Sung Kim (Committee Member)Mark Chapleau (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Human Toxicology
- Date degree season
- Spring 2024
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007483
- Number of pages
- xi, 44 pages
- Copyright
- Copyright 2024 Nafis Md Irfan
- Language
- English
- Date submitted
- 04/23/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 41-44).
- Public Abstract (ETD)
Heart disease is the leading cause of death in the United States. Heart disease is associated with cardiac remodeling that includes cardiac hypertrophy (increase in heart cell size), cardiac fibrosis (scarring of heart tissue), cardiac dysfunction and inflammation. In this study, isoproterenol (ISO) was administered to rats to induce cardiac remodeling, dysfunction, and inflammation. and Alamandine- a relatively new heptapeptide in the renin angiotensin system family was administered to a subgroup of rats infused with ISO to determine if it can protect against cardiac remodeling and improve heart function. Study results revealed that alamandine attenuated ISO-induced cardiac dysfunction, hypertrophy and fibrosis. Moreover, alamandine attenuated inflammatory makers and immune cell deposition in heart induced by ISO. In addition, alamandine prevented the ISO-induced increased expression of angiotensin converting enzyme and angiotensin type 1 receptor in heart. Taken together, the study results suggest that alamandine has the potential to treat heart disease.
- Academic Unit
- Interdisciplinary Studies Program
- Record Identifier
- 9984647647202771
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