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The Pathogenesis of Myocardial Fibrosis in the Setting of Diabetic Cardiomyopathy

Juan Asbun, MD, PhD^_* and Francisco J. Villarreal, MD, PhD^,_*

^_* Escuela Superior de Medicina del Instituto Politécnico Nacional, Mexico City, Mexico
Department of Medicine, University of California, San Diego, California

View larger version (9K): [in a new window]   Figure 1 Production of collagen crosslinks. Glucose interacts with collagen to form a Schiff base. This reaction occurs fast and is reversible. The collagen Schiff base can then rearrange over a period of days to generate an Amadori product (i.e., glycated collagen). This step occurs faster in the forward than in the reverse direction and, thus, glycated collagen accumulates. Glycated collagen can undergo further chemical modification to yield complex compounds and crosslinks known as advanced glycosylation end-products (AGEs). Collagen AGEs are known to be more stable, virtually irreversible, and more resistant to proteolysis.

View larger version (24K): [in a new window]   Figure 2 Sorbitol signaling pathway proposed for high-glucose–mediated enhanced collagen production in fibroblasts. Increases in intracellular glucose concentrations can activate an enhancer sequence in the collagen promoter, yielding enhanced collagen production and fibrosis. Increases in diacylglycerol can occur secondary to the altered transcription of enzymes involved in its synthesis or degradation (e.g., diacylglycerol kinase). The enhanced entry of glucose into the fibroblasts can also occur independently of transporter proteins yielding the stimulation of sorbitol and the production of 3-deoxyglucosone and glyoxal (intracellular advanced glycosylation end-product [AGEs]), both of which are direct stimulants of protein kinase C-beta. The production of aldose reductase (AR) also can be favored by an enhanced transcription of the gene. The sorbitol pathway can also increase production of reactive oxygen species (ROS), further stimulating PKC-beta. GLUT-1 = glucose transporter-1; PKA = protein kinase A.

View larger version (29K): [in a new window]   Figure 3 Diacylglycerol (DAG) signaling pathway proposed for high-glucose–mediated enhanced production of extracellular matrix (ECM) proteins in fibroblasts. High glucose can affect the manner in which fibroblasts respond to angiotensin II. Angiotensin II AT1 receptor levels increase in cells treated with high glucose. The stimulation of AT1 receptors increases the intracellular concentration of DAG. The enzyme in charge of the interconversion of this messenger DAG kinase (DAGK) favors the synthesis of other lipid mediators, which can enter the pathway for the synthesis of dihydroacetone, increase reactive oxygen species, and stimulate protein kinase C (PKC)-beta and/or protein kinase A (PKA). Dihydroacetone can also generate DAG via the action of phosphatidic acid phosphatase (PAP). There also may be protein kinase-independent effects mediated via AT1 receptors, which may alter the production and/or activity of matrix metalloproteinases (MMPs) or other ECM-related genes. Phosphofructokinase (PFK1) is a rate-limiting enzyme involved in the hexosamine pathway. GLUT-1 = glucose transporter-1; MAPK = mitogen-activated protein kinase; NF-B = nuclear factor kappa B; PLCß = phospholipase C beta.