Rationale We previously reported that type VI collagen deposition increases in the infarcted myocardium in vivo. To date, a specific role for this non-fibrillar collagen has not been explored in the setting of myocardial infarction (MI). Objective To determine whether deletion of type VI collagen in an in vivo model of post-MI wound healing would alter cardiac function and remodeling in the days to weeks after injury. Methods and Results Wild type (WT) and Col6a1-/- mice were subjected to MI followed by serial echocardiographic and histological assessments. At 8 weeks post-MI, infarct size was significantly reduced, ejection fraction was significantly preserved (43.9 ± 3.3% vs. 29.1 ± 4.3% for WT) and left ventricular (LV) chamber dilation was attenuated in the Col6a1-/- MI group (25.8 ± 7.9% increase vs. 62.6 ± 16.5% for WT). The improvement in cardiac remodeling was evident as early as 10 days post-MI in the Col6a1-/- mice. Myocyte apoptosis within the infarcted zones was initially greater in the Col6a1-/- group 3 days post-MI but by day 14 this was significantly reduced. Collagen deposition was also reduced in the infarcted and remote areas of the Col6a1-/- hearts. The reductions in chronic myocyte apoptosis and fibrosis are critical events leading to improved long-term remodeling and functional outcomes. Conclusions These unexpected results demonstrate for the first time that deletion of type VI collagen in this knockout model plays a critical protective role following MI by limiting infarct size, chronic apoptosis, aberrant remodeling and fibrosis leading to preservation of cardiac function.
We determined if prolonged isoproterenol (Iso) infusion in rats impaired the ability of the β2-adrenergic agonist terbutaline to increase alveolar liquid clearance (ALC). We infused rats with Iso (at rates of 4, 40, or 400 μg · kg−1 · h−1) or vehicle (0.001 N HCl) for 48 h using subcutaneously implanted miniosmotic pumps. After this time, the rats were anesthetized, and ALC was determined (by mass-balance after instillation of Ringer lactate containing albumin into the lungs) under baseline conditions and after terbutaline administration. Baseline and terbutaline-stimulated ALC in vehicle-infused rats averaged, respectively, 19.6 ± 1.2% (SE) and 44.7 ± 1.5%/h. The ability of terbutaline to increase ALC was eliminated at 400 μg · kg−1 · h−1 Iso, inhibited by 26% at 40 μg · kg−1 · h−1 Iso, and was not affected by 4 μg · kg−1 · h−1 Iso. β-adrenergic receptor (βAR) density of freshly isolated alveolar epithelial type II (ATII) cells from Iso-infused rats was reduced by the 40 and 400 μg · kg−1 · h−1 infusion rates. These data demonstrate that prolonged exposure to β-agonists can impair the ability of β2-agonists to stimulate ALC and produce ATII cell βAR downregulation.
We previously found that prolonged isoproterenol (Iso) infusion in rats impaired the ability of beta-adrenoceptor (beta-AR) agonists to increase alveolar liquid clearance (ALC). Here, we determined if postreceptor defects in beta-AR signaling contribute to this impairment. Iso was infused using subcutaneous miniosmotic pumps (4, 40, or 400 microg. kg-1. h-1) in rats for 48 h. At this time, forskolin-stimulated ALC was measured by mass balance. Forskolin-stimulated ALC [33.4 +/- 2.1%/h (mean +/- SE) in vehicle-infused rats] was reduced by 25 and 38%, respectively, after the 40 and 400 microg. kg-1. h-1 Iso infusions. The ability of forskolin to increase cAMP was reduced by 70% in alveolar type II (ATII) cells isolated from rats infused with 400 microg. kg-1. h-1 Iso. Additionally, the ability of the stable cAMP analog 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Sp-isomer, to increase ALC (48.7 +/- 3.0% in vehicle-infused rats) was reduced by 25 and 51%, respectively, after the 40 and 400 microg. kg-1. h-1 infusions. Finally, the ability of cAMP to increase protein kinase A activity was eliminated in ATII cells isolated from rats infused with Iso at 400 microg. kg-1. h-1. These data demonstrate that prolonged beta-AR agonist exposure can impair alveolar epithelial beta-AR signaling downstream of the beta-AR.
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