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Fibrosis, which is defined as excessive accumulation of fibrous connective tissue, contributes to the pathogenesis of numerous diseases involving diverse organ systems. Cardiac fibrosis predisposes individuals to myocardial ischemia, arrhythmias and sudden death, and is commonly associated with diastolic dysfunction. Histone deacetylase (HDAC) inhibitors(More)
Persistent accumulation of monocytes/macrophages in the pulmonary artery adventitial/perivascular areas of animals and humans with pulmonary hypertension has been documented. The cellular mechanisms contributing to chronic inflammatory responses remain unclear. We hypothesized that perivascular inflammation is perpetuated by activated adventitial(More)
Primary pulmonary hypertension (PPH) is a disease of unknown etiology characterized by lumen-obliterating endothelial cell proliferation and vascular smooth muscle hypertrophy of the small precapillary pulmonary arteries. Because the vascular lesions are homogeneously distributed throughout the entire lung, we propose that a tissue fragment of the lung is(More)
BACKGROUND Severe pulmonary hypertension constitutes a group of diseases characterized by complex, lumen-occluding vascular lesions that develop in genetically susceptible persons. The only viral infection associated with severe pulmonary hypertension has been that due to human immunodeficiency virus type 1, but neither the viral genome nor viral antigens(More)
Primary pulmonary hypertension (PPH) is a frequently fatal disease whose pathobiology is poorly understood. Monoclonal endothelial cell growth is present within plexiform lesions of patients with PPH but not secondary PH because of congenital heart malformations. We hypothesized that endothelial cells within PPH plexiform lesions harbor mutations permissive(More)
Dysfunctional endothelial cells have a central and critical role in the initiation and progression of severe pulmonary hypertension. The elucidation of the mechanisms involved in the control of endothelial cell proliferation and cell death in the pulmonary vasculature, therefore, is fundamentally important in the pathogenesis of severe pulmonary(More)
The vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and is composed of a variety of cells, including fibroblasts, immunomodulatory cells (dendritic cells and macrophages), progenitor cells, vasa(More)
RATIONALE Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with associated right ventricular cardiac remodeling are poorly understood. OBJECTIVE This study was performed to assess the utility of selective(More)
RATIONALE Pulmonary hypertensive remodeling is characterized by excessive proliferation, migration, and proinflammatory activation of adventitial fibroblasts. In culture, fibroblasts maintain a similar activated phenotype. The mechanisms responsible for generation/maintenance of this phenotype remain unknown. OBJECTIVE We hypothesized that aberrant(More)
The recent discoveries of the familial primary pulmonary hypertension gene and somatic mutations in key cell growth and cell death regulatory genes in primary pulmonary hypertension have added a new dimension to severe pulmonary hypertension research. These findings have already impacted on how the disease is viewed, and ultimately, how severe pulmonary(More)