Abstract
BACKGROUND:
Despite achieving target blood pressure, hypertensive individuals have an elevated risk of cardiovascular disease, likely due to unresolved inflammation. Thus, adjunctive immune-modulating therapies are needed to protect patients with hypertension from end-organ damage. We previously showed that T helper 17 cells, which produce the proinflammatory cytokine IL (interleukin)-17A, contribute to hypertensive tissue injury. ROCK2 (Rho-associated coiled-coil–containing protein kinase 2) is a molecular switch governing T helper cell differentiation by promoting T helper 17 polarization and inhibiting T regulatory cell polarization. The present study tests whether T-cell–specific deletion of
Rock2
or the Food and Drug Administration–approved ROCK2-specific inhibitor KD025/belumosudil protects against hypertension-associated end-organ damage.
METHODS:
T-cell–specific
Rock2
knockout mice (
Rock2
fl/fl
CD4
Cre+
) and
Rock2
fl/fl
littermate controls were subjected to a 21-day deoxycorticosterone acetate–salt model of hypertension. In parallel, KD025/belumosudil treatment (50 mg/kg per day) starting after day 10 in wild-type mice was used to test the therapeutic potential of targeting ROCK2. Blood pressure, cardiac fibrosis, renal injury, and infiltration of immune cells were assessed.
RESULTS:
T-cell–specific
Rock2
deletion in mice attenuated the hypertensive response in the deoxycorticosterone acetate–salt model and protected from cardiac and aortic fibrosis. KD025/belumosudil treatment did not reduce blood pressure but did decrease proinflammatory T helper 17 polarization in vivo and increased the cardiac regulatory T cells/T helper 17 ratio. Despite no blood pressure change, KD025 reduced cardiac and aortic fibrosis, improved echocardiographic and invasive hemodynamic indices, and attenuated albuminuria and renal T-cell infiltration.
CONCLUSIONS:
ROCK2 inhibition may serve as an adjunct immune-modulating therapy to mitigate the end-organ damage that occurs in the heart, vasculature, and kidney in hypertension.