Goralatide is an endogenous tetrapeptide secreted by bone marrow and is ubiquitously found in plasma and various tissues. Goralatide is degraded specifically by ACE, and its plasma level rises substantially during ACE inhibitor therapy. Goralatide inhibits the proliferation of isolated cardiac fibroblasts but significantly stimulates the proliferation of vascular smooth muscle cells. Flow cytometry of rat cardiac fibroblasts treated with Goralatide shows significant inhibition of the progression of cells from G0/G1 phase to S phase of the cell cycle. In cardiac fibroblasts transfected with a Smad-sensitive luciferase reporter construct, Goralatide decreases luciferase activity by 55%. Moreover, phosphorylation and nuclear translocation of Smad2 is decreased in cardiac fibroblasts treated with Goralatide. Goralatide is a negative regulator of hematopoietic stem cell proliferation. Goralatide is involved in the control of hematopoietic stem cell proliferation by preventing their recruitment into S-phase. Goralatide appears to exert this function by blocking the action of a stem cell-specific proliferation stimulator and acts selectively on quiescent progenitors. Goralatide inhibits collagenase expression and activation is associated with increased expression of TIMP-1 and TIMP-2. Goralatide does not alter collagenase or gelatinase activity in cardiac fibroblasts under basal conditions, but blunts the IL-1β-induced increase in total collagenase activity. Similarly, Goralatide normalizes the IL-1β-mediated increase in MMP-2 and MMP-9 activities and MMP-13 expression.