Abstract 1432: Loss of SPARC Results in Increased Cardiac Rupture and Heart Failure After Acute Myocardial Infarction
The matricellular protein SPARC (secreted protein acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interaction during matrix remodelling after tissue injury. However, whether SPARC is necessary for proper cardiac remodelling after myocardial infarction (MI) is not yet determined. Therefore, we investigated cardiac healing and function in SPARC wild-type (WT) and SPARC knock-out (KO) mice at 3, 7 and 14 days after MI by permanent ligation of the left coronary artery. First, we showed increased SPARC protein expression from day 3 on, further increasing at day 7 and day 14, mainly located in (myo)fibroblasts, indicating a role in infarct healing and matrix remodelling . Absence of SPARC in mice resulted in fatal cardiac rupture in 80 % of male SPARC KO, whereas only 15 % of male WT mice ruptured. None of the female mice ruptured. Hemodynamic measurements in female mice revealed impaired systolic and diastolic function in SPARC KO vs. WT mice (max. +dP/dT/systolic BP: KO vs WT; 81.25±6.06 vs. 98.20±2.84, P<0.05; max. -dP/dT/systolic BP: KO vs. WT; 60.0±2.33 vs. 71.09±5.07, P<0.05, n=7–11) at 14 days after MI. Histological analysis revealed adverse infarct healing in SPARC KO mice (% necrotic cardiomyocytes: 1.17±0.40% in KO vs. 3.56±0.92% in WT, P<0.05), further characterized by clear disorganisation of the granulation tissue and interstitial matrix. Electromicroscopical analysis confirmed a strongly misaligned and disorganized matrix in SPARC KO vs. WT mice at 14 days. Since SPARC functions as a co-factor for transforming growth factor-beta (TGFβ), which is involved in matrix deposition after MI, we investigated TGFβ signalling in isolated cardiac fibroblasts and showed that lentiviral mediated knockdown of SPARC by short hairpin RNA attenuated TGFβ-induced phosphorylation of SMAD2. Taken together, increased expression of SPARC after MI plays a crucial role in mediated proper cardiac healing, matrix remodelling and in preserving cardiac function.