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Toll-like receptor and its roles in myocardial ischemic/reperfusion injury.

Fang Y, Hu J - Med. Sci. Monit. (2011)

Bottom Line: TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs).TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses.In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.<br />

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular and Thoracic Surgery, 2nd Xiangya Hospital, Central South University, Changsha, China.

ABSTRACT
The innate immune system, mediated via toll-like receptors (TLRs), represents the first line of defensive mechanisms that protects hosts from invading microbial pathogens. TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses. TLR4 is a paramount type of TLRs, located in the heart, and plays an important role in mediating myocardial ischemic reperfusion (I/R) injury. Loss-of-function experiments and animal models using genetic techniques have found that the MyD88-independent and the MyD88-dependent pathways together participate in the pathological process of myocardial I/R injury. Some other distinctive signaling pathways, such as the PI3K/AKt and AMPK/ERK pathways, interacting with the TLR4 signaling pathway, were also found to be causes of myocardial I/R injury. These different pathways activate a series of downstream transcriptional factors, produced a great quantity of inflammatory cytokines, such as IL, TNF, and initiate inflammatory response. This results in cardiac injury and dysfunction, such as myocardial stunning, no reflow phenomenon, reperfusion arrhythmias and lethal reperfusion injury, and other related complication such as ventricular remodeling. In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.

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Related in: MedlinePlus

Crystal structure of the TV8 hybrid of human TLR4 and hagfish VLRB.61. (The picture is supplied by NCBI protein structure database, PDB 2Z63).
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f1-medscimonit-17-4-ra100: Crystal structure of the TV8 hybrid of human TLR4 and hagfish VLRB.61. (The picture is supplied by NCBI protein structure database, PDB 2Z63).

Mentions: The ectodomians of TLRs are mainly composed of LRRs of differing sizes and abundances and are considered to play a prominent role in the promotion of ligand-receptor interaction in a variety of biological settings. The LRR family, which are subdivided into 7 groups using LRR hybrid technology [19], share a highly conserved 11-residue tandem repeat modular sequence (L××L×L××N×L) and horseshoe-like 3D structures (Figure 1). The “×” residue in this sequence is exposed toward the concave surfaces of the horseshoe-like structure mediating interaction with ligands [19–32]. The “asparagines ladder” is another key characteristic of the LRR family [31–33]. The TLRs ectodomians form a relatively rigidly curved solenoid or spring shape, and gain flexibility to some degree by virtue of irregular loops (hinges) of the structure. The first several residues of each LRR form a short beta-strand, which is aligned in the overall structure to form a beta-sheet. The entire structure is bent, with the beta-sheet forming a concave surface, and stabilized by both an asparagines ladder and a hydrophobic interaction. The solenoid architecture that extends from the cell surface forms an arc in which the N-terminus bends back toward the membrane. The ends of the solenoid are capped with disulfide bond motifs that isolate the hydrophobic residues from the surrounding aqueous environment [20,21,24].


Toll-like receptor and its roles in myocardial ischemic/reperfusion injury.

Fang Y, Hu J - Med. Sci. Monit. (2011)

Crystal structure of the TV8 hybrid of human TLR4 and hagfish VLRB.61. (The picture is supplied by NCBI protein structure database, PDB 2Z63).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3539509&req=5

f1-medscimonit-17-4-ra100: Crystal structure of the TV8 hybrid of human TLR4 and hagfish VLRB.61. (The picture is supplied by NCBI protein structure database, PDB 2Z63).
Mentions: The ectodomians of TLRs are mainly composed of LRRs of differing sizes and abundances and are considered to play a prominent role in the promotion of ligand-receptor interaction in a variety of biological settings. The LRR family, which are subdivided into 7 groups using LRR hybrid technology [19], share a highly conserved 11-residue tandem repeat modular sequence (L××L×L××N×L) and horseshoe-like 3D structures (Figure 1). The “×” residue in this sequence is exposed toward the concave surfaces of the horseshoe-like structure mediating interaction with ligands [19–32]. The “asparagines ladder” is another key characteristic of the LRR family [31–33]. The TLRs ectodomians form a relatively rigidly curved solenoid or spring shape, and gain flexibility to some degree by virtue of irregular loops (hinges) of the structure. The first several residues of each LRR form a short beta-strand, which is aligned in the overall structure to form a beta-sheet. The entire structure is bent, with the beta-sheet forming a concave surface, and stabilized by both an asparagines ladder and a hydrophobic interaction. The solenoid architecture that extends from the cell surface forms an arc in which the N-terminus bends back toward the membrane. The ends of the solenoid are capped with disulfide bond motifs that isolate the hydrophobic residues from the surrounding aqueous environment [20,21,24].

Bottom Line: TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs).TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses.In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.<br />

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular and Thoracic Surgery, 2nd Xiangya Hospital, Central South University, Changsha, China.

ABSTRACT
The innate immune system, mediated via toll-like receptors (TLRs), represents the first line of defensive mechanisms that protects hosts from invading microbial pathogens. TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses. TLR4 is a paramount type of TLRs, located in the heart, and plays an important role in mediating myocardial ischemic reperfusion (I/R) injury. Loss-of-function experiments and animal models using genetic techniques have found that the MyD88-independent and the MyD88-dependent pathways together participate in the pathological process of myocardial I/R injury. Some other distinctive signaling pathways, such as the PI3K/AKt and AMPK/ERK pathways, interacting with the TLR4 signaling pathway, were also found to be causes of myocardial I/R injury. These different pathways activate a series of downstream transcriptional factors, produced a great quantity of inflammatory cytokines, such as IL, TNF, and initiate inflammatory response. This results in cardiac injury and dysfunction, such as myocardial stunning, no reflow phenomenon, reperfusion arrhythmias and lethal reperfusion injury, and other related complication such as ventricular remodeling. In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.

Show MeSH
Related in: MedlinePlus