Role of the cytoskeleton in the development of a hypofibrotic cardiac fibroblast phenotype in volume overload heart failure

Abstract

Hemodynamic load regulates cardiac remodeling. In contrast to pressure overload (increased afterload), hearts subjected to volume overload (VO; preload) undergo a distinct pattern of eccentric remodeling, chamber dilation, and decreased extracellular matrix content. Critical profibrotic roles of cardiac fibroblasts (CFs) in postinfarct remodeling and in response to pressure overload have been well established. Little is known about the CF phenotype in response to VO. The present study characterized the phenotype of primary cultures of CFs isolated from hearts subjected to 4 wk of VO induced by an aortocaval fistula. Compared with CFs isolated from sham hearts, VO CFs displayed a “hypofibrotic” phenotype, characterized by a ~50% decrease in the profibrotic phenotypic markers α-smooth muscle actin, connective tissue growth factor, and collagen type I, despite increased levels of profibrotic transforming growth factor-β1 and an intact canonical transforming growth factor-β signaling pathway. Actin filament dynamics were characterized, which regulate the CF phenotype in response to biomechanical signals. Actin polymerization was determined by the relative amounts of G-actin monomers versus F-actin. Compared with sham CFs, VO CFs displayed ~78% less F-actin and an increased G-actin-to-F-actin ratio (G/F ratio). In sham CFs, treatment with the Rho kinase inhibitor Y-27632 to increase the G/F ratio resulted in recapitulation of the hypofibrotic CF phenotype observed in VO CFs. Conversely, treatment of VO CFs with jasplakinolide to decrease the G/F ratio restored a more profibrotic response (>2.5-fold increase in α-smooth muscle actin, connective tissue growth factor, and collagen type I). NEW & NOTEWORTHY The present study is the first to describe a “hypofibrotic” phenotype of cardiac fibroblasts isolated from a volume overload model. Our results suggest that biomechanical regulation of actin microfilament stability and assembly is a critical mediator of cardiac fibroblast phenotypic modulation.

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

“…Mechanical stretch in response to volume overload may affect gene expression in both interstitial cells and cardiomyocytes. Fibroblasts from volume overloaded hearts exhibited a "hypofibrotic phenotype", characterized by reduced collagen and α-SMA synthesis 190 . It has been suggested that increased oxidative stress induced by mechanical stretch may activate an autophagic degradation of procollagen in volume overloaded hearts 191 .…”

Fibroblasts in the Infarcted, Remodeling, and Failing Heart

“…Studies in experimental models of chordal rupture–induced mitral regurgitation in the dog 163, 164 and of aortocaval fistula in the rat 165, 166 suggest that volume overload causes unique interstitial perturbations that may contribute to adverse remodeling. In contrast to the marked increase in collagen deposition noted in pressure-overloaded hearts, the volume-overloaded myocardium exhibits a marked loss of interstitial collagen associated with increased MMP expression 163, 164, reduced collagen synthesis (167), and accentuated collagen degradation 166, 168. The matrix-degrading phenotype of interstitial cells in volume-overloaded hearts has been attributed to release of cardiomyocyte-derived TNF-α (165) or to downmodulation of TGF-β signaling (163).…”

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

“…As a result, we found that the differential bestclassifier proteins Low-HF-active/High-HF-inactive point towards an important role for actin nucleation and polymerization mechanisms in drug response (reflected by the functions regulation of actin nucleation, regulation of Arp2/3 complex-mediated actin nucleation, SCAR complex, filopodium tip, or dendrite extension). In fact, the alteration of actin nucleation and polymerization mechanisms has been reported in heart failure [38][39][40]. Interestingly, a role for the activation of another differential best-classifier candidate, ATGR2, has been proposed to mediate some of the beneficial effects of angiotensin II receptor type 1 antagonists, such as valsartan [41,42].…”