Lumican is a small proteoglycan which sits in the extracellular matrix. It has been strongly associated with HCM in the past, but no-one has provided a clear, detailed description of what it may be doing in the disease.
Lumican is broadly located in any type of fibrosis in HCM; these include the different types of fibrosis (interstitial, replacement or perivascular) and different stages of fibrosis (early fibrosis to late, severe fibrosis). We show that the increase in lumican in HCM correlates strongly with the increase in fibrillar collagen in HCM.
Fibrillar collagen, and collagen I specifically, is the most abundant structural protein in the heart and in cardiac fibrosis. The results show lumican’s strong relationship with collagen I, and find the two are colocalized throughout areas of fibrosis.
We apply dSTORM super-resolution microscopy in a novel manner to characterize the cardiac ECM; showing that this relationship between lumican and collagen I extends all the way to the very earliest stages of fibrotic remodelling. Most importantly, we show that adding lumican to cardiac fibroblast cultures (cell cultures mimicking the cardiac ECM) promotes reorganization of thin, diffusely spread collagen fibers into thicker, accumulated collagen fiber structures. Such stiffer, thicker collagen fibers would increase stiffness in cardiac fibrosis significantly.
Our main conclusions are that lumican’s primary role in HCM is likely through its strong relationship to collagen I in fibrosis and that it promotes reorganization of collagen into larger, pathological macrostructures.