Research Project
10127753
Cardiovascular disease (CVD) is the leading cause of death of women in the United States, accounting for around 1 of every 3 deaths. Estrogen deficiency, as seen in aging women or after oophorectomy, has been linked to loss of cardiovascular protection, typically seen during reproductive life. Up to half of women evaluated for myocardial ischemia have normal appearing coronary arteries. These women can develop heart failure with a preserved ejection fraction (termed HFpEF) for which the etiology is unclear. Hormonal replacement therapy (HRT) after menopause remains controversial but current evidence cannot support this for either primary or secondary prevention of CVD. There are clearly modulatory influences on estrogenic signaling, that could well influence cardiovascular health in later life. Previous studies have demonstrated that estrogen improves energy production within the heart by increasing 5' adenosine monophosphate-activated protein (AMPK) and mitochondrial biogenesis via upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?); a master switch of mitochondrial function, linked to vascular integrity and angiogenesis. Estrogen has been also found to modulate purinergic signaling by boosting expression of adenosine receptors and of CD39, the dominant endothelial ecto-ADPase that generates adenosine. There are also close relationships between purinergic signaling and dipeptidyl peptidase-4 (DPP-4; otherwise known as adenosine deaminase complexing protein 2 or CD26), possibly mediated by adenosine deaminase bioactivity. Decreased PGC-1? and aberrant purinergic signaling in metabolic syndrome may lead to impaired mitochondrial function, provoking diastolic dysfunction, and also result in impaired angiogenesis. We hypothesize there are central roles of PGC-1?, purines and DPP-4 linked neuropeptide pathways in the control of angiogenesis and mitochondrial activity. These become increasingly disordered in setting of estrogen loss provoking development of metabolic syndrome, thereby exacerbating HFpEF and microvascular disease. Specific Aim 1: To determine how ischemia and cardiometabolic dysfunction in women's heart disease are exacerbated by the loss of puringeric pathways from estrogen deficiency. We expect to determine that diastolic dysfunction is a functional consequence of this microvascular loss and cardiometabolic dessynchrony. Specific Aim 2: To evaluate the role of adenosingergic receptor activation and DPPIV inhibition on angiogenesis in a ovariectomized swine model of chronic myocardial ischemia and metabolic syndrome. Here, we will explore relationships between the regulated and linkages in the exocytosis of nucleotides and neuropeptides, formation of nucleosides (adenosine) and alterations in angiogenic activity secondary to these. Summary: We will study fundamental mechanisms in heart disease underpinning biological differences in women. We will also offer new therapeutic strategies that target cardiac metabolism, HFpEF and the microvasculature to bolster benefits of estrogen in postmenopausal hearts.
