Although once considered functionally homogeneous, resident cardiac fibroblasts may consist of distinct populations that program to different phenotypes in response to myocardial injury. Some antihypertensive drugs have been shown to induce apoptosis in 30% of resident fibroblasts, while also limiting the degree of cardiac fibrosis. Moreover, the reduction in fibroblast number and the protection against myocardial injury- induced excessive collagen accumulation persists for up to two weeks after stopping drug treatment. Together, these findings suggest that resident cardiac fibroblasts consist of a mixture of populations and that removal of an adverse fibroblast population improves cardiac responses to injury. Identifying a pathogenic subset of cardiac fibroblasts is therefore critical for the development of targeted anti-fibrotic therapies. Cardiac fibroblasts represent an ideal target for slowing or preventing fibrosis as they have a primary role in regulating collagen production and degradation. The long-term research goal of this project is to directly inform the development and translation of novel anti-fibrotic strategies that precisely target an aberrant subset of fibroblasts for the prevention and treatment of cardiovascular disease and heart failure. The overall objective of this application is to identify the subset of resident cardiac fibroblasts that can be deleted to render the heart resistant to development of cardiac fibrosis. Thus, the central hypothesis of this proposal is that the reduction in fibrosis induced by some antihypertensive medications is due to apoptotic deletion of a unique subpopulation of resident fibroblasts that are hyperproliferative and promote excessive collagen production. The rationale for these studies is that once an aberrant subset of fibroblasts that is responsible for excessive fibrosis and inflammation is identified, targeted therapies can be developed to prevent the progression from early cardiovascular disease to heart failure. The proposed studies will determine the extent to which blocking drug- induced fibroblast apoptosis limits the protection against future development of fibrosis (Aim 1), elucidate a genomic signature to identify the fibroblasts that are both susceptible to drug-induced apoptosis and are particularly fibrogenic (Aim 2), and determine the phenotype of the cells remaining following deletion of a subset of cardiac fibroblasts (Aim 3). A multidisciplinary approach employing in vivo and in vitro methodologies will be used to determine the obligatory nature of cardiac fibroblast apoptosis in producing long-term protection against pathological fibrotic remodeling and to identify the subset of cells that may play a primary role in excessive collagen deposition in progressing heart disease. These anticipated findings are expected to have a positive impact because they will create the opportunity for the development of fibroblast-targeted therapies for the treatment, and ultimately prevention, of the fibrotic remodeling underlying heart disease.
The proposed research is relevant to public health because fibrosis (the scarring of injured tissue) plays a major role in the development and progression of heart disease ? the leading cause of death among Americans. The proposed studies will provide a greater understanding of the cells that cause and regulate fibrosis processes in the heart. Thus, the proposed research is relevant to the part of NHLBI's mission that pertains to developing new treatment strategies to protect the heart and slow or prevent progression to heart failure ? a condition that affects 5.2 million Americans.
