Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality in the United States. There is evidence that premenopausal women are much less prone to suffer CVD than males of similar age, and that this advantage disappears after menopause. Using a mouse model of myocardial infarction (MI), we recently found that female mice had a much lower cardiac rupture rate and better preserved left ventricular (LV) function than males after MI. Supplementation of estrogen and/or castration in males reduced the rupture rate and slowed LV remodeling, while supplementation of testosterone in females increased the incidence of rupture and worsened cardiac function and remodeling, indicating a protective role of estrogen and detrimental role of testosterone post-MI. In this proposal, we will further test the hypotheses that estrogen, acting on the alpha-receptors, protects the heart from early (infarct expansion and cardiacrupture) and late remodeling (cardiac hypertrophy, dilatation and dysfunction) and this effect is partially mediated by facilitating the healing process during acute MI, and by inhibiting the inflammatory response and reducing oxidative stress during the development of heart failure. Conversely, testosterone exacerbates the inflammatory response.
In Aim 1, we will study the effect of estrogen and testosterone on infarct healing, including inflammatory cell infiltration, collagenase activity, collagen deposition, infarct expansion and neovascularization.
In Aim 2, we will study whether, during the chronic phase of MI, estrogen decreases nuclear factor-kappaB and reactive oxygen species, thereby ameliorating the inflammatory response and improving cardiac function in males, whereas testosterone aggravates inflammation and cardiac dysfunction.
In Aim 3, we will study whether the cardioprotective effect of estrogen is mediated by activation of its alpha-receptor.
In Aim 4, we will study whether 1) estrogen given soon after ovariectomy (mimics early postmenopausal status) will provide better cardiac protection than if it is given a few weeks later (mimics late postmenopausal status) when mice are subjected to MI; and 2) the cardioprotective effect of estrogen will be attenuated when combined with progestin.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078951-04
Application #
7329835
Study Section
Special Emphasis Panel (ZRG1-MIM (01))
Program Officer
Liang, Isabella Y
Project Start
2004-12-15
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
4
Fiscal Year
2008
Total Cost
$273,076
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Yang, Xiao-Ping; Reckelhoff, Jane F (2011) Estrogen, hormonal replacement therapy and cardiovascular disease. Curr Opin Nephrol Hypertens 20:133-8
Meng, Xiaomei; Dai, Xiangguo; Liao, Tang-Dong et al. (2011) Dose-dependent toxic effects of high-dose estrogen on renal and cardiac injury in surgically postmenopausal mice. Life Sci 88:178-86
Xu, Jiang; Carretero, Oscar A; Liao, Tang-Dong et al. (2010) Local angiotensin II aggravates cardiac remodeling in hypertension. Am J Physiol Heart Circ Physiol 299:H1328-38
Wang, Fangfei; He, Quan; Sun, Ying et al. (2010) Female adult mouse cardiomyocytes are protected against oxidative stress. Hypertension 55:1172-8
Zhu, Liping; Carretero, Oscar A; Liao, Tang-Dong et al. (2010) Role of prolylcarboxypeptidase in angiotensin II type 2 receptor-mediated bradykinin release in mouse coronary artery endothelial cells. Hypertension 56:384-90
Ardanaz, Noelia; Yang, Xiao-Ping; Cifuentes, M Eugenia et al. (2010) Lack of glutathione peroxidase 1 accelerates cardiac-specific hypertrophy and dysfunction in angiotensin II hypertension. Hypertension 55:116-23
Xu, Jiang; Carretero, Oscar A; Shesely, Edward G et al. (2009) The kinin B1 receptor contributes to the cardioprotective effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in mice. Exp Physiol 94:322-9
Sun, Ying; Carretero, Oscar A; Xu, Jiang et al. (2009) Deletion of inducible nitric oxide synthase provides cardioprotection in mice with 2-kidney, 1-clip hypertension. Hypertension 53:49-56
Zhan, Enbo; Keimig, Thomas; Xu, Jiang et al. (2008) Dose-dependent cardiac effect of oestrogen replacement in mice post-myocardial infarction. Exp Physiol 93:982-93
Wang, Fangfei; Keimig, Thomas; He, Quan et al. (2007) Augmented healing process in female mice with acute myocardial infarction. Gend Med 4:230-47

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