New Insights Into Heat Shock Protein 90 in the Pathogenesis of Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a multifactorial and progressive disorder. This disease is characterized by vasoconstriction and vascular remodeling, which results in increased pulmonary artery pressure and pulmonary vascular resistance. Although extensive studies have been carried out to understand the etiology, it is still unclear what intracellular factors contribute and integrate these pathological features. Heat shock protein 90 (Hsp90), a ubiquitous and essential molecular chaperone, is involved in the maturation of many proteins. An increasing number of studies have revealed direct connections between abnormal Hsp90 expression and cellular factors related to PAH, such as soluble guanylate cyclase and AMP-activated protein kinase. These studies suggest that the Hsp90 regulatory network is a major predictor of poor outcomes, providing novel insights into the pathogenesis of PAH. For the first time, this review summarizes the interplay between the Hsp90 dysregulation and different proteins involved in PAH development, shedding novel insights into the intrinsic pathogenesis and potentially novel therapeutic strategies for this devastating disease.

Keywords: AMP-activated protein kinase; heat shock protein 90; novel therapeutic options; pathogenesis; pulmonary arterial hypertension; soluble guanylate cyclase.

FIGURE 1

Domain structure of Hsp90 family members in humans. Schematic representation of the domain structure of Hsp90 isoforms together with the biological functions of each domain.

FIGURE 2

Hsp90 chaperone cycle. Open conformation state is likely to be the most efficient at binding client proteins. Addition of ATP altering the relationship between the NTD and MD, resulting in a transient NTD/MD conformation. Co-chaperones assist in loading client proteins onto Hsp90. Aha1 increases Hsp90 ATPase activity, contributing to the closing of the NTD. Client proteins would remain bound due to the hydrophobic surfaces still present on the MD and CTD. Client proteins are folded during the process of NTD closure. Finally, nucleotide hydrolysis results in the very compact ADP state and the release of client proteins. Open conformation of the Hsp90 NTD is restored for the next chaperone cycle.

FIGURE 3

Structures of Hsp90 inhibitors.

FIGURE 4

Overview of the important roles of Hsp90 in the regulation of sGC and AMPK involved in the pathogenesis of PAH. Hsp90 drives heme insertion into apo-sGCβ after the complex of Hsp90 and apo-sGCβ formation. Meanwhile, Hsp90 also prevents apo-sGCβ’s premature interaction with sGCα to form a heme-free, non-functional sGC heterodimer. Hsp90 dissociates from sGCβ once heme insertion is complete, allowing holo-sGCβ to partner with sGCα and to form a mature and functional sGC heterodimer. AMPK is a client of Hsp90, and Hsp90 interferes with the function of the AMPK complex by mediating the phosphorylation of AMPK in PASMCs. Activation of AMPK in PAECs assists the complex formation between eNOS and Hsp90, promoting eNOS-mediated NO production.

FIGURE 5

Proposed mechanism graph shows that the combination of Hsp90 inhibitors and sGC activators may lead to better treatment of PAH via relaxing blood vessels and inhibiting vascular remodeling.