The Rho kinases ROCK1 and ROCK2 have nonoverlapping roles in pulmonary arterial hypertension (PAH), according to a new study published in Biochemical and Biophysical Research Communications.

“Our study supports the further elucidation of ROCK1 and ROCK2 functions, and the development of selective ROCK inhibitors as potential novel therapeutic agents in [pulmonary hypertension] and related pulmonary diseases,” the authors of the study said.

Vascular smooth muscle (VSM)-targeted homozygous ROCK1-knockout (KO) mice had normal embryonic development and grew normally to adulthood. When exposed to hypoxic conditions, ROCK1-KO mice presented with lower mean right ventricular systolic pressure (RVSP) compared to wild-type (WT) mice, albeit similar to normoxic ROCK1-KO or WT mice. These findings suggest that ROCK1-KO mice might have a blunted pulmonary vascular pressure response to hypoxia.


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“The significantly blunted RVSP response of the VSM ROCK1 KO strain to [Sugen5416]/hypoxia compared to WT demonstrates for the first time that VSM ROCK1 plays a significant role in hypoxia-induced PH development that is separate from that of VSM ROCK2,” the authors said.

Moreover, ROCK1-KO mice may present a reduced right ventricle (RV) hypertrophic response in hypoxic conditions. ROCK1-KO mice exposed to hypoxic conditions showed lower mean value on the Fulton index (which allows for the assessment of RV hypertrophy), as well as a tendency for decreased RV mass/body weight ratio, when compared to WT mice exposed to the same conditions, but similar values to normoxic ROCK1-KO or WT mice.

On the other hand, ROCK1-KO mice and WT mice had shown a similar increase in pulmonary small vessel neomuscularization in response to hypoxia.

ROCK1 knockdown in human idiopathic PAH pulmonary artery smooth muscle cells (PASMC) did not alter cell growth. However, the authors found that ROCK1 mediates serotonin actions, with ROCK1 knockdown leading to reduced AKT and MYPT1 signaling in serotonin-treated cells.

In contrast to the findings for ROCK1, VSM-targeted ROCK2 haplo-insufficient mice were found in previous studies to be protected from hypoxia-induced PH development.

Reference

Penumatsa KC, Singhal AA, Warburton RR, et al. Vascular smooth muscle ROCK1 contributes to hypoxia-induced pulmonary hypertension development in mice. Biochem Biophys Res Commun. 2022;604:137-143. doi:10.1016/j.bbrc.2022.02.064