Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2567497 | Pulmonary Pharmacology & Therapeutics | 2011 | 14 Pages |
Abstract
Pulmonary hypertension (PH) is a general term comprising a spectrum of pulmonary hypertensive disorders which have in common an elevation of mean pulmonary arterial pressure (mPAP). The prototypical form of the disease, termed pulmonary arterial hypertension (PAH), is a rare but lethal syndrome with a complex aetiology characterised by increased pulmonary vascular resistance (PVR) and progressive elevation of mPAP; patients generally die from heart failure. Current therapies are inadequate and median survival is less than three years. PH due to chronic hypoxia (CH) is a condition separate from PAH and is strongly associated with chronic obstructive pulmonary disease (COPD). An early event in the pathogenesis of this form of PH is hypoxic pulmonary vasoconstriction (HPV), an acute homeostatic process that maintains the ventilation-perfusion ratio during alveolar hypoxia. The mechanisms underlying HPV remain controversial, but RhoA/Rho kinase (ROK)-mediated Ca2+-sensitisation is considered important. Increasing evidence also implicates RhoA/ROK in PASMC proliferation, inflammatory cell recruitment and the regulation of cell motility, all of which are involved in the pulmonary vascular remodelling occurring in all forms of PH. ROK is therefore a potential therapeutic target in treating PH of various aetiologies. Here, we examine current concepts regarding the aetiology of PAH and also PH due to CH, focusing on the contribution that RhoA/ROK-mediated processes may make to their development and on ROK inhibitors as potential therapies.
Keywords
NFATPAECBMPR-IIPASMCHPAHIPAHPPHNPAHSMCmonocrotalineVOCCSMARho kinaseROKSmooth muscle cellPulmonary arterial smooth muscle cellEndothelial cellPulmonary arteryNuclear Factor of Activated T CellsSmooth muscle α-actinheritable pulmonary arterial hypertensionPulmonary arterial hypertensionfasudilChronic hypoxiahypoxic pulmonary vasoconstrictionHPVPulmonary hypertensionPersistent pulmonary hypertension of the newbornIdiopathic pulmonary arterial hypertensionVoltage-gated potassium channelvoltage-operated calcium channel
Related Topics
Health Sciences
Medicine and Dentistry
Pulmonary and Respiratory Medicine
Authors
Michelle J. Connolly, Philip I. Aaronson,