Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart.
When considering the pathological steps in the progression from cardiac overload towards the full clinical syndrome of heart failure, it is becoming increasingly clear that the extracellular matrix (ECM) is an important determinant in this process. Chronic pressure overload induces a number of structural alterations, not only hypertrophy of cardiomyocytes but also an increase in ECM proteins in the interstitium and perivascular regions of the myocardium. When this culminates in excessive fibrosis, myocardial compliance decreases and electrical conduction is affected. Altogether, fibrosis is associated with an increased risk of ventricular dysfunction and arrhythmias. Consequently, anti-fibrotic strategies are increasingly recognized as a promising approach in the prevention and treatment of heart failure. Thus, dissecting the molecular mechanisms underlying the development of cardiac fibrosis is of great scientific and therapeutic interest. In this review, we provide an overview of the available evidence supporting the general idea that fibrosis plays a causal role in deteriorating cardiac function. Next, we will delineate the signalling pathways importantly governed by transforming growth factor β (TGFβ) in the control of cardiac fibrosis. Finally, we will discuss the recent discovery that miRNAs importantly regulate cardiac fibrosis.
Creemers
Esther E
EE
Heart Failure Research Center, Academic Medical Center, Meibergdreef 15, Room L2-108-3, 1105 AZ Amsterdam, The Netherlands. e.e.creemers@amc.uva.nl
Pinto
Yigal M
YM
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D035683:MicroRNAs; D016212:Transforming Growth Factor beta