Myofibroblast-mediated mechanisms of pathological remodelling of the heart

Abstract

The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection.

Liver fibrosis score predicts mortality in heart failure patients with preserved ejection fraction

“…HF and chronic liver disease) 29, 30. Collagen‐dependent ventricular stiffness is increased in HFpEF 1, 2, 3, 4, 5. The cardiac extracellular matrix is predominantly composed of fibrillar collagen type I (85%) and type III (11%) 29.…”

“…It has several pathophysiological aspects including cardiac hypertrophy and interstitial fibrosis1, 2, 3, 4, 5 and/or impaired functional reserve of multiple organs, such as lungs, vessels, skeletal muscle, kidney, and liver 1, 2, 6. The abdominal compartment (e.g.…”

MicroRNA‐30c suppresses the pro‐fibrogenic effects of cardiac fibroblasts induced by TGF‐β1 and prevents atrial fibrosis by targeting TGFβRII

“…TGF‐β1 is considered the major growth factor directly promoting myofibroblast development by inducing expression of α‐SMA. The transformation of fibroblasts into myofibroblasts is a critical event in the genesis of cardiac fibrosis 62, 63. During cardiac fibrosis, CFs underwent phenotypic transition to myofibroblasts marked by increased α‐SMA, which is a reliable and classic marker for the myofibroblast 33, 34, 35.…”

TGF-β1 Increases Resistance of NIH/3T3 Fibroblasts Toward Apoptosis Through Activation of Smad2/3 and Erk1/2 Pathways

“…2,9,14,[29][30][31] Briefly, cells were plated at the indicated density using complete cell culture media (10% fetal bovine serum) and incubated overnight at 95% air/5% carbon dioxide to allow attachment. Subsequently, cells were transferred into an incubation media with low serum (2.5%) for sensitization toward exogenous growth factors.…”

“…17 It is important to understand mechanisms underlying excessive fibrosis and identify targets to prevent such complications to reduce morbidity and mortality associated with the growing epidemic of aging-associated diseases. 2,4,12,14,[18][19][20][21][22][23] Transforming growth factor-β1 (TGF-β1), a profibrotic cytokine, has a variable effect on cell survival and proliferation depending on the cell type and clinical condition, with both proapoptotic and antiapoptotic effects previously described. 24 The effect of TGF-β1 receptor activation on differentiation and maturation of fibroblasts is mediated through two intracellular signaling pathways: 1) canonical, Smad-dependent, and 2) noncanonical, Erk1/2-dependent.…”