A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling

Abstract

Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here, we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling.

Figure 1

Schematic overview of the main events that contribute to cardiac remodeling. Among the multiple signaling pathways involved, the increase in cell death, inflammation, and oxidative stress pathways, as well as alterations in energy metabolism, converge in cardiomyocyte (CMs) loss, hypertophy, and myocardial fibrosis, leading to cardiac remodeling. The main consequence in such structural modifications is heart failure.

Figure 2

Cardiac hypertrophy (a) and cardiac fibrosis (b) signaling pathways. Several molecules participate in the modulation of genes involved in cardiac hypertrophy. The transcription factor NFAT, responsible for cardiac hypertrophy, is positively regulated through calmodulin/calcineurin. In contrast, GSK3β inhibits cytoplasm-nucleus translocation of NFAT. HDAC4/HDAC5 also represses transcriptional activity of hypertrophic signals. Angiotensin II is the main mediator of cardiac fibrosis; AT1 receptor and ROS lead to TGFβ activation. This latter, through a SMAD-dependent or -independent pathway, activates the fibrotic genetic program, which consists in fibroblast proliferation, leukocyte infiltration, matrix degradation, collagen deposition, and myofibroblastic transdifferentiation.

Figure 3

Schematic overview of the relationship between PPAR-response elements (PPREs) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in cardiac remodelling. AKT: protein kinase B; AMPK: adenosine monophosphate-activated protein kinase; ERK1/2: extracellular signal-regulated kinase 1/2; ERR: estrogen-related receptor; GPCR: G-protein coupled receptor; GSK3β: glycogen synthase kinase 3 beta; IKK: IκB kinase; IκB: inhibitor of NF-κB; INSR: insulin receptor; IRS: insulin receptor substrate; LATS 1/2: serine/threonine-protein kinase 1/22; LKB1: liver kinase B1; MEK: mitogen-activated protein kinase kinase; MSK1: mitogen and stress-related kinase 1; MST1: mammalian sterile 20-like kinase; mTORC: mammalian target of rapamycin complex 1 and mTORC-2; ORAI1/3: calcium release-activated calcium channel protein 1/3; PDC: pyruvate dehydrogenase complex; PDK4: pyruvate dehydrogenase kinase; PDP1: pyruvate dehydrogenase phosphatase1; PI3K: phosphoinositide 3 kinase; PI3K: phosphoinositide 3-kinase; RAF: serine/threonine-specific protein kinases; RAS: small GTPase RAS; RHEB: RAS homolog enriched in brain; RXR: 9-cis-retinoic acid receptor; S6 K1: S6 kinase 1; STIM-1: stromal interaction molecule-1; TSC-1/2: tuberous sclerosis- 1/2; YAP: yes-associated protein. See text for details. The figure was made in part using tools provided by Servier Medical Arts.