Hypertension
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The activation of angiotensin II type 2 receptor (AT2R) has been considered cardioprotective. However, there are controversial findings regarding the role of overexpressing AT2R in the heart. Using transgenic mice with different levels of AT2R gene overexpression in the heart (1, 4, or 9 copies of the AT2R transgene: Tg1, Tg4, or Tg9), we studied the effect of AT2R overexpression on left ventricular remodeling and dysfunction post-myocardial infarction (MI). ⋯ These pathological responses were diminished in Tg1 and Tg4 mice. Moreover, the protective effects of AT2R were abolished by AT2R antagonist and also absent in Tg9 mice. We thus conclude that whether overexpression of AT2R is beneficial or detrimental to the heart is largely dependent on expression levels and possibly via regulations of Nox2 and transforming growth factor β1 signaling pathways.
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Angiotensin II induces cardiovascular injury, in part, by activating inflammatory response; however, the initial factors that trigger the inflammatory cascade remain unclear. Microarray analysis of cardiac tissue exposed to systemic angiotensin II infusion revealed that extracellular heterodimeric proteins S100a8/a9 were highly upregulated. The increase in S100a8/a9 mRNA of CD11b(+)Gr1(+) neutrophils isolated from both the peripheral blood and heart was highest on day 1 of angiotensin II infusion and decreased to baseline at day 7. ⋯ Consequently, recombinant S100a8/a9-treated CFs promoted migration of monocytes and CFs, whereas neutralizing S100a9 antibody blocked S100a9 or receptor for advanced glycation end products-suppressed cellular migration. Finally, administration of a neutralizing S100a9 antibody prevented angiotensin II infusion-induced nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, subsequent perivascular and interstitial fibrosis, and hypertrophy in heart. Our findings identify neutrophil-produced S100a8/a9 as an initial proinflammatory factor needed to trigger inflammation and cardiac injury during acute hypertension.
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Clinical observations suggest that postmenopausal women have a higher incidence of aneurysmal rupture than premenopausal women. We hypothesize that a relative deficiency in estrogen may increase the risks of aneurysmal growth and subarachnoid hemorrhage in postmenopausal women. We assessed the effects of estrogen and selective estrogen receptor subtype agonists on the development of aneurysmal rupture in ovariectomized female mice. ⋯ The protective role of estrogen receptor-β agonist was abolished by the inhibition of nitric oxide synthase. We showed that estrogen prevented aneurysmal rupture in ovariectomized female mice. The protective effect of estrogen seemed to occur through the activation of estrogen receptor-β, a predominant subtype of estrogen receptor in human intracranial aneurysms and cerebral arteries.
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Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with significant morbidity and mortality in patients with various lung and heart diseases. PAH is characterized by vascular obstruction which leads to a sustained increased pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy and failure. Limited PAH therapies indicate that novel approaches are urgently needed for the treatment of PAH. ⋯ Moreover, endothelial cell apoptosis and endothelial-to-mesenchymal transition occurred in the lungs of MCT-treated wild-type mice and were restored in IκBα mutant+MCT mice, indicating an association with NF-κB signaling. In lung microvascular endothelial cells, IκBα (AA) mutant plasmid restored the decreased bone morphogenetic protein receptor 2 protein level and reversed the endothelial-to-mesenchymal transition process induced by transforming growth factor-β1. We conclude that NF-κB regulates bone morphogenetic protein receptor 2-inhibitor of differentiation-Notch-3 axis genes and the subsequent endothelial cell apoptosis and endothelial-to-mesenchymal transition events in the lungs, providing new mechanistic information about MCT-induced PAH and right ventricular hypertrophy.