Framing Heartaches: The Cardiac ECM and the Effects of Age
Abstract
:1. Age and the Cardiac Extracellular Matrix—A Relationship That Needs More Attention
2. Components of the Cardiac ECM
2.1. Epimysium, Perimysium, Endomysium and the Basement Membrane
2.2. Glycoproteins of the Cardiac ECM
2.2.1. Collagen
2.2.2. SPARC
2.2.3. Fibronectin
2.2.4. Elastin
2.2.5. Laminin
2.2.6. Tenascin
2.2.7. Hyaluronan
2.3. Proteoglycans—Decorin, Biglycan and Periostin
2.4. Matrikines
Structure and Location | Functions | References | |
---|---|---|---|
Epimysium, perimysium and endomysium | Thin, fibrous sheets. The epimysium surrounds the whole heart. The perimysium surrounds groups of cardiomyocytes. The endomysium surrounds individual cardiomyocytes. | Protection of the cardiomyocytes. Facilitates supply of nutrients by housing vasculature. | [11] |
Basement membrane | Lamina lucida: Adjacent to the ECM. Consists mainly of laminins. Lamina densa: Adjacent to the cardiomyocytes. Consists mainly of collagen type IV. | Protection and support of individual cardiomyocytes. Aids cellular alignment, polarity and organisation, adhesion and migration. Enables cells to sense mechanical stimuli. Regulates electrical conduits. Facilitates cellular integrity by forming a semi-permeable membrane. | [12,13,14,15,16] |
Collagen type I and III | Fibrillar collagens. Crosslinked. | Collagen type I lends strength and resilience, aids isolation of electrical currents. Collagen type III enhances flexible properties. | [19,20,21,22] |
Collagen type IV and VI | Non-fibrillar collagens. | Collagen type IV is essential for the functions of the BM. Collagen type VI forms a mesh supporting collagen type I and III. | [13,24,26] |
Fibronectin | Large (440–450 kDa), with several glycosylation sites and isomers. | Cellular adhesion, forms a framework which collagen is deposited upon and aids cellular communication. | [31,32,33,34] |
Elastin | Disordered form in between contractions. Undergoes rapid crosslinking when stretched. Highly hydrophobic. | Aids elasticity to the heart. | [35,36] |
Laminin | Large (several hundred kDa), with 3 domains forming a cross shape. | Connects proteins in the ECM and the BM; see Figure 1 for an overview of how laminin interacts with several different proteins. | [37,39] |
Tenastinc | Large proteins (180–250 kDa) with several isotypes. | Mainly expressed during embryonic development and upregulated during injury. Interferes with the actions of fibronectin. | [40,41,42] |
Hyaluronan | Anionic, nonsulphated glycosaminoglycan (GAG) | Adds shock absorbing properties to the ECM. Involved in wound healing, immune responses, cellular proliferation and migration. An excess of HA leads to an increased differentiation of myofibroblasts. | [44,45,46,47] |
Decorin and biglycan | Core proteins surrounded by one chondroitin sulphate or dermatan sulphate. | Decorin modulates collagen type I and III by “decorating” the fibrils. These interactions between the proteins are essential for stability of the ECM. It also interacts with TGF-β through competitive binding, further affecting the ECM. Biglycan has the same functions, but studies have shown they are not interchangeable. | [52,53,54,55,56,57,58,59,60] |
Periostin | Relatively large protein of ~90 kDa | Regulates collagen type I fibrillogenesis. Associated with differentiation of fibroblasts into myofibroblasts. | [61,62] |
Matrikines | Varies. The result of incomplete proteolytic cleavage of different ECM proteins such as fibronectin. [63] | Varies. The function is often different from that of the original ECM protein. Glycyl-L-histodyl-L-lysine (GHK) is an important matrikine example. It is involved in stimulation of collagen type I, GAGs and MMP production. | [67,68,69,71] |
3. Remodelling of the Cardiac ECM—The Role of Fibroblasts, MMPs and TIMPs
4. Changes with Age
4.1. Fibrosis
4.2. Increased Inflammation—The Involvement of Immune Cells and ROS
4.3. Altered Protein Levels in the ECM
4.4. Collagens and SPARC Changes with Age
Changes with Age | Species | Anatomical Structure | References | |
---|---|---|---|---|
Collagen, overall | Increases | Mice, sheep, rats, humans, dogs | Left ventricle, atria, left atria | [27,106,107,108,109,115,116,117] |
Collagen type I | Increases | Humans, sheep | Left ventricle | [27,111,112,113,114,115,116,117,118] |
Collagen type III | Decreases in humans | Humans | Left ventricle | [118] |
Collagen type IV and VI | Increases | Mice | Left ventricle | [116] |
Fibronectin | Increases in mice, decreases in hamsters and rats | Mice, hamsters, rats | Left ventricle, left ventricle and atria in rats | [104,106,109] |
Lminin | β1: Increases. Β2: Decreases | Mice | Left ventricle | [108] |
Integrin | α1, α5: Increases. β1: Decreases | Mice | Left ventricle | [106] |
Mimecan | Decreases | Mice | Whole hearts and left ventricle from females | [105,109] |
SPARC | Increases | Sheep, mice | Left ventricle | [27,111] |
Change with Age | Species | Anatomical Structure | References | |
---|---|---|---|---|
Collagen type I and III | Decreases in rats and hamsters. No change in sheep. No change in murine atria. | Rats, sheep and Syrian hamsters | Atria and ventricles. | [107,110,111,113] |
Fibronectin | Decreases | Rats, hamsters, mice | Atria and ventricles. | [106,107,110] |
4.5. Changes in MMPs and TIMPs with Age
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Ringström, N.; Edling, C.; Nalesso, G.; Jeevaratnam, K. Framing Heartaches: The Cardiac ECM and the Effects of Age. Int. J. Mol. Sci. 2023, 24, 4713. https://doi.org/10.3390/ijms24054713
Ringström N, Edling C, Nalesso G, Jeevaratnam K. Framing Heartaches: The Cardiac ECM and the Effects of Age. International Journal of Molecular Sciences. 2023; 24(5):4713. https://doi.org/10.3390/ijms24054713
Chicago/Turabian StyleRingström, Nathalie, Charlotte Edling, Giovanna Nalesso, and Kamalan Jeevaratnam. 2023. "Framing Heartaches: The Cardiac ECM and the Effects of Age" International Journal of Molecular Sciences 24, no. 5: 4713. https://doi.org/10.3390/ijms24054713