CCR5 as a Treatment Target in Pulmonary Arterial Hypertension
Background—Pulmonary arterial hypertension (PH), whether idiopathic or related to underlying diseases such as HIV infection, results from complex vessel remodeling involving both pulmonary-artery smooth muscle cell (PA-SMC) proliferation and inflammation. CCR5, a co-receptor for cellular HIV-1 entry expressed on macrophages and vascular cells, may be involved in the pathogenesis of PH. Maraviroc is a new CCR5 antagonist designed to block HIV entry.
Methods and Results—Marked CCR5 expression was found in lungs from patients with idiopathic PH, in mice with hypoxia-induced PH and in SIV-infected macaques, in which it was chiefly localized in the PA-SMCs. To assess the role for CCR5 in experimental PH, we used both gene disruption and pharmacological CCR5 inactivation in mice. Because maraviroc does not bind to murine CCR5, we used human-CCR5ki mice for pharmacological and immunohistochemical studies. Compared to wild-type mice, CCR5-/- mice or human-CCR5ki mice treated with maraviroc exhibited decreased PA-SMC proliferation and recruitment of perivascular and alveolar macrophages during hypoxia exposure. CCR5-/- mice reconstituted with wild-type bone-marrow cells and wild-type mice reconstituted with CCR5-/- bone-marrow cells were protected against PH, suggesting CCR5-mediated effects on PA-SMCs and macrophage involvement. The CCR5 ligands CCL5 and the HIV-1 gp120 protein increased intracellular calcium and induced growth of human and h-CCR5ki mouse PA-SMCs; maraviroc inhibited both effects. Maraviroc also reduced the growth-promoting effects of conditioned media from CCL5-activated macrophages derived from human-CCR5ki mice on PA-SMCs from wild-type mice.
Conclusions—The CCL5-CCR5 pathway represents a new therapeutic target in PH associated with HIV or with other conditions.
- Received April 29, 2014.
- Revision received June 20, 2014.
- Accepted June 27, 2014.