Adverse cardiac remodeling mediated by the altered expression of versican (15.7)

Abstract

Adverse remodeling following myocardial infarction (MI) is the primary pathologic process that leads to heart failure. The process is driven by normal repair mechanisms that become uncontrolled. This research focuses on the functional significance of the extracellular matrix molecule versican (Vcan) in regulating adverse remodeling and the deposition of insoluble fibrillar collagen outside of the infarct border zone. Our hypothesis is that adverse remodeling is mediated by an aberrant increase in Vcan deposition that promotes an increased presence of fibrocytes, cells expressing myeloid origin CD45+ and Hsp47+, into the injured as well as non‐inured myocardium. To test this hypothesis, we have experimentally induced MI by coronary ligation and compared WT, Vcan deficient (Vcan(tim1Zim)) and Cav1 null (a model of adverse remodeling) mice for expression of Vcan and the presence of fibrocytes within the injured and non‐injured myocardium. We show that in the WT Vcan is up regulated as part of the normal repair at the infarct borders. This expression pattern is accompanied by an increased infiltration of CD45+ cells within the Vcan rich boarder zone. Interestingly, in the Vcan depletion model, we measured significant reduced average injured wall thickness (247 vs. 394 µm), less infiltration of fibrocytes and an unexpected reduction of collagen deposition. In Cav1 null mice, Vcan is up regulated leading to a more widespread distribution of fibrocytes, associated with adverse remodeling after MI. A better understanding of adverse remodeling after MI will contribute to the development of extracellular matrix based interventions designed to reduce or prevent the morbid effects of post‐infarction remodeling.Grant Funding Source: NHLBI R01HL66231 (CHM), Janey Briscoe Center for Excellence in Cardiovascular Research (CJLS)