A study on the comparative and combinatorial efficacy of resveratrol with angiotensin-converting enzyme inhibitor and angiotensin receptor blocker/neprilysin inhibitor in myocardial infarction
| dc.contributor.author | Raj, Pema | |
| dc.contributor.examiningcommittee | Pierce, Grant (Physiology and Pathophysiology) Jassal, Davinder (Physiology and Pathophysiology) Wigle, Jeffrey (Biochemistry and Medical Genetics) Anand-Srivastava, Madhu (Université de Montréal) | en_US |
| dc.contributor.supervisor | Netticadan, Thomas (Physiology and Pathophysiology) Zieroth, Shelley (Physiology and Pathophysiology) | en_US |
| dc.date.accessioned | 2019-10-23T18:10:47Z | |
| dc.date.available | 2019-10-23T18:10:47Z | |
| dc.date.issued | 2019 | en_US |
| dc.date.submitted | 2019-10-15T17:01:35Z | en |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Myocardial infarction (MI) and heart failure are the two major health care burdens around the world. Resveratrol, a plant polyphenol, is well-documented for its benefits in the setting of MI. However, it is also important to understand the comparative and combinatorial efficacy of resveratrol alongside the established therapies to translate the pre-clinical findings to the clinical setting. In the first study, left anterior descending coronary artery ligated (MI-induced) and sham-operated male Sprague Dawley rats were treated with vehicle, resveratrol, angiotensin-converting enzyme inhibitor perindopril, or a combination of both for 8 weeks. Echocardiography was performed to assess the cardiac structure and function. MI rats treated with resveratrol, perindopril and a combination of both had significantly reduced left ventricular (LV) dilatation and improved LV ejection fraction (LVEF). Resveratrol, perindopril and a combination of both significantly decreased cardiac oxidative stress, inflammation and fibrosis and improved the activity of antioxidant enzymes in MI rats. In the second study, MI-induced and sham-operated rats received vehicle, angiotensin receptor blocker/neprilysin inhibitor sacubitril/valsartan, angiotensin receptor blocker valsartan, resveratrol or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented LV dilatation and improved LVEF in MI rats. Resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol also significantly reduced oxidative stress, inflammation and brain natriuretic peptide in MI rats. In the final study, adult rat cardiomyocytes were pre-treated with resveratrol or left untreated and exposed to norepinephrine (NE). NE-exposure resulted in significant cardiomyocyte contractile dysfunction, reduced cell viability and an increase in oxidative stress. Resveratrol significantly improved contractile function and cell viability and reduced oxidative stress in NE-exposed adult rat cardiomyocytes. Pharmacological inhibition of superoxide dismutase (SOD) and Forkhead Box 1 (FOXO1) resulted in a loss of resveratrol mediated protection in NE-exposed adult rat cardiomyocytes. Resveratrol also prevented the proliferation of adult rat cardiac fibroblasts. In conclusion, resveratrol treatment improves cardiac structure and function equivalent to perindopril, valsartan, and sacubitril/valsartan in MI rats and the combination treatment is also effective. Resveratrol protects NE-exposed adult rat cardiomyocytes by a mechanism contingent upon SOD/FOXO1 and reduces cardiac fibroblast proliferation. | en_US |
| dc.description.note | February 2020 | en_US |
| dc.identifier.citation | Raj P, Louis XL, Thandapilly SJ, Movahed A, Zieroth S, Netticadan T. Potential of resveratrol in the treatment of heart failure. Life sciences. 2014;95(2):63-71 | en_US |
| dc.identifier.citation | Raj P, Zieroth S, Netticadan T. An overview of the efficacy of resveratrol in the management of ischemic heart disease. Annals of the New York Academy of Sciences. 2015; 1348 (1):55-67. | en_US |
| dc.identifier.citation | Raj P, Aloud BM, Louis XL, Yu L, Zieroth S, Netticadan T. Resveratrol is equipotent to perindopril in attenuating post-infarct cardiac remodeling and contractile dysfunction in rats. The Journal of nutritional biochemistry. 2016; 28: 155-63. | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/34344 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Resveratrol | en_US |
| dc.subject | Angiotensin-converting enzyme inhibitor | en_US |
| dc.subject | Angiotensin receptor blocker/neprilysin inhibitor | en_US |
| dc.subject | Myocardial infarction | en_US |
| dc.subject | Heart failure | en_US |
| dc.title | A study on the comparative and combinatorial efficacy of resveratrol with angiotensin-converting enzyme inhibitor and angiotensin receptor blocker/neprilysin inhibitor in myocardial infarction | en_US |
| dc.type | doctoral thesis | en_US |