Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload

Abstract

Myocardial fibrosis is an integral component of most cardiac pathologic conditions and contributes to the development of both systolic and diastolic dysfunction. Because of the availability of genetically manipulated animals, mouse models are essential for understanding the mechanisms involved in the pathogenesis of cardiac fibrosis. Accordingly, we characterized the inflammatory and fibrotic response in a mouse model of cardiac pressure overload due to transverse aortic constriction (TAC). Following TAC, mouse hearts exhibited induction of chemokines and proinflammatory cytokines, associated with macrophage, but not neutrophil, infiltration. Induction of inflammatory cytokines was followed by a late upregulation of Transforming Growth Factor (TGF)-β isoforms, activation of the Smad2/3 and Smad1/5 pathways, induction of matricellular proteins, and deposition of collagen. Inflammatory activity decreased after 28 days of TAC; at this timepoint established fibrosis was noted, accompanied by ventricular dilation and systolic dysfunction. Late induction of inhibitory mediators, such as TGF-β may play an essential role in the transition from inflammation to fibrosis by suppressing inflammatory gene synthesis while inducing matrix deposition. Our findings identify molecular mediators and pathways with a potential role in cardiac fibrosis laying the foundations for studies exploring the pathogenesis of fibrotic cardiac remodeling using genetically targeted mice.

Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan

“…The signaling cascade of TGF-b activation, including the phosphorylation of Smad2/3, has been well characterized. Although we did not examine TGF-b activation in the PO heart, a previous study demonstrated late induction of TGF-b1 in the PO heart, 41 and our real-time RT-PCR results confirmed these data. In addition, serum TGF-b1 levels were better attenuated by olmesartan than hydralazine in our model (data not shown), suggesting that olmesartan treatment reduced TGF-b induction in our rat model.…”

“…10 Another group reported that SB203580, a p38 mitogen-activated protein kinase inhibitor, diminished Ang II-induced Smad2 phosphorylation. 40 Xia et al 41 reported activation of the Smad signaling pathway after aortic constriction in a transverse aortic constriction model and Gao et al 42 reported activation of the Smad signaling pathway in the Ang IIinfused heart. These data suggest that the Smad pathway might be associated with CTGF induction in the PO heart.…”

Short-term ACE inhibition confers long-term protection against target organ damage

“…24 Mast cells, 25 macrophages 26 and T cells 27 have all been found at the site of active remodeling and cytokines released from these cells can promote collagen deposition and fibroblast proliferation. In animal models of pressure overloadinduced LV hypertrophy, a transient increase in cytokine release and macrophage infiltration 28 has been shown, and Hsieh et al 29 have demonstrated that NOS inhibition with L-NAME in hypertensive rats increases vascular inflammation. Although previous studies have demonstrated that ACE inhibitor treatment reduces macrophage infiltration and cellular proliferation following myocardial infarction, 30 the present study is the first to demonstrate that these beneficial effects persist well after stopping treatment.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…Pressure overload is associated with profound and dynamic changes in the composition of the ECM; these changes regulate geometry and function, not only by affecting the mechanical properties of the ventricle, but also by modulating cellular responses. In animal models, activation of cardiac fibroblasts is one of the earliest effects of pressure overload in the myocardium, ultimately leading to deposition of collagenous matrix and expansion of the interstitium (99)(100)(101). In human patients, hypertensive heart disease is associated with development of interstitial and periarteriolar fibrosis even in the absence of significant coronary atherosclerosis (102).…”