Caveolin-1, Inflammation, Interstitial fibrosis, Macrophage polarization, Myocardial infarction, Transforming growth factor β1 (TGF-β1)
Digital Object Identifier (DOI)
Adverse remodeling following myocardial infarction (MI) leading to heart failure is driven by an imbalanced resolution of inflammation. The macrophage cell is an important control of post-MI inflammation, as macrophage subtypes secrete mediators to either promote inflammation and extend injury (M1 phenotype) or suppress inflammation and promote scar formation (M2 phenotype). We have previously shown that the absence of caveolin-1 (Cav1), a membrane scaffolding protein, is associated with adverse cardiac remodeling in mice, but the mechanisms responsible remain to be elucidated. We explore here the role of Cav1 in the activation of macrophages using wild type C57BL6/J (WT) and Cav1tm1Mls/J (Cav1-/-) mice. By echocardiography, cardiac function was comparable between WT and Cav1-/- mice at 3days post-MI. In the absence of Cav1, there were a surprisingly higher percentage of M2 macrophages (arginase-1 positive) detected in the infarcted zone. Conversely, restoring Cav1 function after MI in WT mice by adding back the Cav1 scaffolding domain reduced the M2 activation profile. Further, adoptive transfer of Cav1 null macrophages into WT mice on d3 post-MI exacerbated adverse cardiac remodeling at d14 post-MI. In vitro studies revealed that Cav1 null macrophages had a more pronounced M2 profile activation in response to IL-4 stimulation. In conclusion, Cav1 deletion promotes an array of maladaptive repair processes after MI, including increased TGF-β signaling, increased M2 macrophage infiltration and dysregulation of the M1/M2 balance. Our data also suggest that cardiac remodeling can be improved by therapeutic intervention regulating Cav1 function during the inflammatory response phase.
Was this content written or created while at USF?
Citation / Publisher Attribution
Journal of Molecular and Cellular Cardiology, v. 76, p. 84-93
This article is the post-print author version. Final version available at: https://doi.org/10.1016/j.yjmcc.2014.07.020
Scholar Commons Citation
Shivshankar, Pooja; Halade, Ganesh V.; Calhoun, Cheresa; Escobar, Gladys P.; Mehr, Ali J.; Jimenez, Fabio; Martinez, Cindy; Bhatnagar, Harshita; Mjaatvedt, Corey H.; Lindsey, Merry L.; and Le Saux, Claude Jourdan, "Caveolin-1 Deletion Exacerbates Cardiac Interstitial Fibrosis by Promoting M2 Macrophage Activation in Mice after Myocardial Infarction" (2014). Internal Medicine Faculty Publications. 48.