The roles of ROCK1 and ROCK2 in cardiopulmonary and fibrotic disease: considerations for pan-ROCK inhibition as a therapeutic approach

INTRODUCTION: The Rho-associated protein kinase (ROCK) isoforms, ROCK1 and ROCK2, are central regulators of cellular functions fundamental to the pathogenesis of cardiopulmonary and fibrotic diseases. Evidence from animal and cellular models demonstrates ROCK signaling attenuation exerts potent effects on the dysregulated hyperproliferative, fibrotic, and contractile cellular components of the vascular wall and lung parenchyma. These aberrant cellular processes are central to the pathobiology of diverse cardiopulmonary diseases, including pulmonary hypertension and interstitial lung disease, where effective treatment options remain limited. Both pan-ROCK and ROCK2-selective inhibitors are approved for various diseases. The ongoing development of more potent or isoform-selective ROCK inhibitors across emerging indications highlights an unrealized potential. AREAS COVERED: The roles of ROCK1 and ROCK2 in tissue remodeling, inflammatory recruitment, and dysfunction in multiple cell types. Searches utilized keywords: 'pulmonary hypertension' or 'cardiopulmonary fibrosis' AND variations on 'ROCK inhibitor' and hand searching of key publications. EXPERT OPINION: Evidence suggests that pan-ROCK inhibitors may have certain advantages over ROCK2-selective agents for complex cardiopulmonary and fibrotic diseases, as each isoform plays distinct, non-redundant roles in fibrosis and inflammation. Concerns about hypotension as a dose-limiting side effect unique to pan-ROCK inhibition versus ROCK2 inhibition are increasingly unsupported by clinical data.