The Search for Disease-Modifying Therapies in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) and its severe subtype pulmonary arterial hypertension (PAH) encompass a set of multifactorial diseases defined by sustained elevation of pulmonary arterial pressure and pulmonary vascular resistance leading to right ventricular failure and subsequent death. Pulmonary hypertension is characterized by vascular remodeling in association with smooth muscle cell proliferation of the arterioles, medial thickening, and plexiform lesion formation. Despite our recent advances in understanding its pathogenesis and related therapeutic discoveries, PH still remains a progressive disease without a cure. Nevertheless, development of drugs that specifically target molecular pathways involved in disease pathogenesis has led to improvement in life quality and clinical outcomes in patients with PAH. There are presently more than 12 Food and Drug Administration-approved vasodilator drugs in the United States for the treatment of PAH; however, mortality with contemporary therapies remains high. More recently, there have been exuberant efforts to develop new pharmacologic therapies that target the fundamental origins of PH and thus could represent disease-modifying opportunities. This review aims to summarize recent developments on key signaling pathways and molecular targets that drive PH disease progression, with emphasis on new therapeutic options under development.

Keywords: DNA damage; epigenetics; inflammation; metabolism; molecular pathology; proliferation; pulmonary artery hypertension; vascular function.

Figure 1.

Pathogenesis of PAH. Multiple vascular cell types, endothelial cells, smooth muscle cells, and fibroblasts are involved in pulmonary arterial pathobiology. Healthy endothelium modulates the balance between vasodilation and vasoconstriction and inhibits smooth muscle cell proliferation in order to maintain a low-resistance pulmonary vasculature. Pulmonary vasoconstriction has long been regarded as an early event, and excessive pulmonary vasoconstriction has been related to endothelium dysfunction characterized by reduced production of vasodilators (nitric oxide and prostacyclin), along with overexpression of vasoconstrictors (endothelin-1). Abnormal proliferation of smooth muscle cells is the earliest pathobiological features of vascular remodeling, leading to muscularization of peripheral pulmonary arteries and medial hypertrophy in pulmonary muscular arteries. Recruitment of inflammatory cells and progressive migration of smooth muscle cells further results in intimal fibrosis. In the late stage of disease progression, formation of plexiform lesions and in situ thrombus occlude the vessel lumen leads to progressive reduction of the blood flow, thus establishing PAH. PAH indicates pulmonary arterial hypertension.

Figure 2.

Current targets and therapies in PAH. The 4 major pathways, endothelin-1, prostacyclin, NO-sGC-cGMP, and calcium channel signaling involved in the regulation of pulmonary vasomotor tone, are shown. These pathways represent the targets of all currently approved and emerging PAH therapies. A, Endothelin-1 (ET-1) stimulates vasocontraction and proliferation through activation of both ET_A and ET_B receptors on smooth muscle cells. Either selective (ambrisentan) or nonselective (bosentan and macitentan) ET-I receptor antagonists can block the ET-I pathway. B, Prostacyclin activates vasodilation and inhibits proliferation of smooth muscle cells through cAMP-dependent pathway. Prostacyclin and its derivatives (epoprostenol, treprostinil, iloprost, and beraprost) and l-prostanoid (IP) receptor (selexipag) provide therapeutic benefit in PAH. C, Nitric oxide (NO) activates vasodilation and antiproliferation of smooth muscle cells through cGMP-dependent pathway. Inhalation of NO and administration of soluble guanylyl cyclase (sGC) stimulator (riociguat) or phosphodiesterase 5 (PDE5) inhibitors (sildenafil and tadalafil) have been shown effective in the treatment of PAH. D, Subsequent activation of calcium (Ca²⁺) channels and an increase in cytosolic Ca²⁺ free concentration in smooth muscle cells lead to vasoconstriction and proliferation. Calcium channel blockers (nifedipine and diltiazem) have provided therapeutic benefit in patients with PAH who demonstrate a positive response to the vasoreactivity test. AC indicates adenylyl cyclase; BH4, tetrahydrobiopterin; cGMP, guanosine monophosphate; COX, cyclooxygenase; ECEs, endothelin-converting enzymes; eNOS, endothelial NO synthase; FDA, Food and Drug Administration; PAH, pulmonary arterial hypertension.

Figure 3.

Emerging therapeutic targets in PAH. An improved understanding of the molecular and genetic mechanisms leading to PAH have provided translational opportunities for the development and testing of novel therapeutics agents. A number of emerging pathways amenable to therapeutic manipulation are summarized. 5-HT indicates serotonin; AMPK, AMP-activated protein kinase; BET, bromodomain and extra terminal domain; BMP9, bone morphogenetic protein 9; BMPR2, bone morphogenetic protein receptor type 2; CCR5, C-C chemokine receptor 5; DHEA, dehydroepiandrosterone; EC, endothelial cell; EPCs, endothelial progenitor cells; HDAC, histone deacetylases; LTB₄, leukotriene B4; miRNA, microRNA; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; PAH, pulmonary arterial hypertension; PPARγ, peroxisome proliferator-activated receptor γ; ROS, reactive oxygen species; TK, tyrosine kinase; TPH, tryptophan hydroxylase; VIP, vasoactive intestinal peptide.