doi: 10.1161/01.RES.0000204572.65400.a5
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© 2006 American Heart Association, Inc.
Editorials |
Spatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial Hypertension
Heterogeneous BMP Signaling May Have Therapeutic Implications
From the Pulmonary Hypertension Program, University of Alberta, Edmonton, Canada.
Correspondence to Evangelos D. Michelakis, MD, FACC, FAHA, Director, Pulmonary Hypertension Program, University of Alberta, Canada Research Chair in Pulmonary Hypertension, Edmonton, Alberta T6G2B7, Canada. E-mail emichela@cha.ab.ca
See related article, pages 209–217
Key Words: apoptosis • pulmonary circulation • pulmonary hypertension • vascular remodeling • survivin
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
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Introduction |
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"The temptation to form premature theories is the bane of our profession."— Sherlock Holmes
Although pulmonary arterial hypertension (PAH) was originally thought to be a disease of increased pulmonary arterial (PA) tone, we now know that vasoconstriction is important only in a minority of patients.1 PAH is characterized by increased proliferation of PA endothelial cells (PAECs) and PA smooth muscle cells (PASMCs), leading to narrowing or even obliteration of the PA lumen, increased pulmonary vascular resistance (PVR), right ventricular failure and premature death.1
Voelkel and Tuder suggested that the proliferative remodeling in the PAs resembles cancer.2 Several features, in addition to excessive proliferation, make this hypothesis attractive. For example, as in cancer, the development of PAH appears to result from a "multiple-hit" mechanism, where environmental factors (virus, inflammation, anorexigens, shunt-induced shear stress, etc) interact with a genetic predisposition (loss-of-function mutations in the bone morphogenetic protein receptor II, BMPR-II) culminating in disease.1 That PAH is characterized by a cancer-like apoptosis resistance is supported by recent reports that proapoptotic therapies can reverse PAH, similarly to cancer, where proapoptotic chemotherapies are the mainstay of treatment. Several experimental PAH treatments (including dichloroacetate,3 simvastatin,4 sildenafil,5 imatinib,6 anti-survivin,7 and K+ channel replacement gene therapies8) induce apoptosis of PASMCs, leading to reversal of vascular remodeling and PAH. In sharp contrast, strategies designed to promote survival and inhibit apoptosis of PAECs (cell-based gene transfer of angiopoietin-19 or eNOS,10 caspase inhibitors11) also improve PAH, particularly at early stages. These apparently conflicting reports can be rationalized by
Related Article:
Circ. Res. 2006 98: 209-217.
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