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Extracellular Matrix Communication and Turnover in Cardiac Physiology and Pathology

Abhijit Takawale, Siva S.V.P. Sakamuri, Zamaneh Kassiri

10.1002/cphy.c140045

Source: Volume 5, Issue 2, April 2015

Published online: March 2015

Full Article on Wiley Online Library



ABSTRACT

Despite significant advances in treating heart disease, heart failure remains a major cause of morbidity and mortality. Regardless of the initiating cause(s), heart failure is associated with disruptions in the myocardial extracellular matrix (ECM). ECM is a dynamic structure and its physiological turnover is mediated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Research in the past two decades has revealed that the function of ECM extends beyond its role in providing structural support. Similarly, ECM regulatory proteins, MMPs and TIMPs, have been demonstrated to play diverse and ECM‐independent roles in tissue remodeling and homeostasis. ECM is a network structure that in addition to providing structural support, serves as an extracellular reservoir for a number of growth factors and cytokines, and plays a central role in interstitial transport of different molecules (hormones, growth factors, drugs, etc.). This is mainly through the action of nonstructural ECM components, proteoglycans and matricellular proteins, which are also critical in cell‐ECM interactions and overall ECM remodeling. As such, sustaining the ECM integrity is not only critical in preserving cardiac geometry and function, it is essential in ensuring optimal delivery of different molecules to their site of action. Further, ECM composition and integrity in disease should be considered in designing drugs with a specific site of action. In this review article, we provide an overview of the ECM structure, components, its function in interstitial transport, heart disease‐dependent ECM remodeling, and the potential therapeutic approaches in preserving the diseased myocardial ECM and cardiac function. © 2015 American Physiological Society. Compr Physiol 5:687‐719, 2015.

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Figure 1. Figure 1. The steps involved in collagen transcription, translation, and formation of collagen fibers. Collagen is synthesized by cardiac fibroblast which involves a number of intracellular as well as extracellular steps. Once procollagen‐α synthesized in the ribosome, it is imported to the ER where it undergoes hydroxylation and glycoslation by procollagen‐lysine 5‐dioxygenase (PLOD1), prolyl hydroxylase (PHO), and glycosyl transferase (GLT); trimerization and dislufide bonding by protein disulfide isomerase (PDI), and folding to form triple helical structure by peptidylproine cis‐trans‐isomerases (PPIases). Hsp47 helps to maintain the stability of this triple helical structure which is then transported to Golgi apparatus, packed into COPII vesicles, then secreted into the interstitial space. In the extracellular space, the procollgen‐α molecule undergoes posttranslational modifications. N‐ and C‐propeptides are enzymatically removed by ADAMTS and BMP1 respectively, generating PICP, PINP for collagen type I (and PIIICP and PIIINP for collagen type III) which are considered as biomarkers of collagen synthesis. PCOLCE1,2 and sFRP2 enhance the activity of BMP1. LOX mediates oxidative deamination and cross‐linking of collagen fibers and formation of collagen fibril. Matricellular proteins such as OPN, SPARC and decorin contribute to assembly of collagen fibril and finally formation of collagen fibers.
Figure 2. Figure 2. Molecular structure of matrix metalloproteinases (MMPs). General MMP structure includes the hemopexin domain, a hinge, the catalytic domain with a zinc‐binding site, a prodomain that conceals the catalytic domain by a S‐H bond, and a signal peptide domain. Exceptions include MMP7 and MMP26 that lack the hemopexin‐like domain and the hinge. Membrane‐type MMPs include a transmembrane domain (MT1, MT2, MT3, and MT5) or are anchored to the cell membrane by a Glycosylphosphatidylinositol (GPI) (MT5 and MT6 are anchored to the cell membrane). The catalytic domain of gelatinases (MMP2 and MMP9) contains three fibronectin repeats (Fn), and the prodomain in MMP11, ‐28, and the six MTMMPs contain a furin‐cleavage site (Fr).
Figure 3. Figure 3. TIMP2‐dependent cell surface activation of Pro‐MMP2. The membrane bound MT1‐MMP anchors a TIMP2 molecule by binding to its N‐terminus (Hemopexin domain) while a pro‐MMP2 is recruited to the noninhibitory C‐terminus of TIMP2. Catalytic processing of a neighboring MT1‐MMP converts the 72 kDa pro‐MMP2 to its active 64 kDa form.
Figure 4. Figure 4. Myocardial extracellular matrix serves as a reservoir. A number of growth factors and cytokines are stored in the myocardial matrix bound to proteoglycans. They can be released by proteolytic activity of different proteases (e.g., MMPs, ADAMs, and ADAM‐TS), or upon disruption of the matrix in disease.
Figure 5. Figure 5. Activation of TGFβ and its downstream signaling pathways. TGFβ is released into the extracellular space noncovalently bound to LAP (latency associated proprotein) forming the small latent complex (SLC), which is sequestered in the extracellular matrix bound to LTBP (latent TGFβ‐binding protein) and to matrix molecules such as fibrillin and fibronectin. This comprises the large latent complex (LLC). MMP‐mediated cleaved of LTBP release the SLC and subsequently the TGFβ dimer. Activation of TGFβ receptor (TGFβR) can activate the canonical Smad pathway, or the noncanonical mitogen‐activated protein kinases (MAPK), ERK, JNK, and p38.


Figure 1. The steps involved in collagen transcription, translation, and formation of collagen fibers. Collagen is synthesized by cardiac fibroblast which involves a number of intracellular as well as extracellular steps. Once procollagen‐α synthesized in the ribosome, it is imported to the ER where it undergoes hydroxylation and glycoslation by procollagen‐lysine 5‐dioxygenase (PLOD1), prolyl hydroxylase (PHO), and glycosyl transferase (GLT); trimerization and dislufide bonding by protein disulfide isomerase (PDI), and folding to form triple helical structure by peptidylproine cis‐trans‐isomerases (PPIases). Hsp47 helps to maintain the stability of this triple helical structure which is then transported to Golgi apparatus, packed into COPII vesicles, then secreted into the interstitial space. In the extracellular space, the procollgen‐α molecule undergoes posttranslational modifications. N‐ and C‐propeptides are enzymatically removed by ADAMTS and BMP1 respectively, generating PICP, PINP for collagen type I (and PIIICP and PIIINP for collagen type III) which are considered as biomarkers of collagen synthesis. PCOLCE1,2 and sFRP2 enhance the activity of BMP1. LOX mediates oxidative deamination and cross‐linking of collagen fibers and formation of collagen fibril. Matricellular proteins such as OPN, SPARC and decorin contribute to assembly of collagen fibril and finally formation of collagen fibers.


Figure 2. Molecular structure of matrix metalloproteinases (MMPs). General MMP structure includes the hemopexin domain, a hinge, the catalytic domain with a zinc‐binding site, a prodomain that conceals the catalytic domain by a S‐H bond, and a signal peptide domain. Exceptions include MMP7 and MMP26 that lack the hemopexin‐like domain and the hinge. Membrane‐type MMPs include a transmembrane domain (MT1, MT2, MT3, and MT5) or are anchored to the cell membrane by a Glycosylphosphatidylinositol (GPI) (MT5 and MT6 are anchored to the cell membrane). The catalytic domain of gelatinases (MMP2 and MMP9) contains three fibronectin repeats (Fn), and the prodomain in MMP11, ‐28, and the six MTMMPs contain a furin‐cleavage site (Fr).


Figure 3. TIMP2‐dependent cell surface activation of Pro‐MMP2. The membrane bound MT1‐MMP anchors a TIMP2 molecule by binding to its N‐terminus (Hemopexin domain) while a pro‐MMP2 is recruited to the noninhibitory C‐terminus of TIMP2. Catalytic processing of a neighboring MT1‐MMP converts the 72 kDa pro‐MMP2 to its active 64 kDa form.


Figure 4. Myocardial extracellular matrix serves as a reservoir. A number of growth factors and cytokines are stored in the myocardial matrix bound to proteoglycans. They can be released by proteolytic activity of different proteases (e.g., MMPs, ADAMs, and ADAM‐TS), or upon disruption of the matrix in disease.


Figure 5. Activation of TGFβ and its downstream signaling pathways. TGFβ is released into the extracellular space noncovalently bound to LAP (latency associated proprotein) forming the small latent complex (SLC), which is sequestered in the extracellular matrix bound to LTBP (latent TGFβ‐binding protein) and to matrix molecules such as fibrillin and fibronectin. This comprises the large latent complex (LLC). MMP‐mediated cleaved of LTBP release the SLC and subsequently the TGFβ dimer. Activation of TGFβ receptor (TGFβR) can activate the canonical Smad pathway, or the noncanonical mitogen‐activated protein kinases (MAPK), ERK, JNK, and p38.
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Article Title: Extracellular Matrix Communication and Turnover in Cardiac Physiology and Pathology
 

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Abhijit Takawale, Siva S.V.P. Sakamuri, Zamaneh Kassiri. Extracellular Matrix Communication and Turnover in Cardiac Physiology and Pathology. Compr Physiol 2015, 5: 687-719. doi: 10.1002/cphy.c140045