Abstract:
BACKGROUND:Inflammatory serine proteases (ISPs) play an important role in cardiac repair after injury through hydrolysis of dead cells and extracellular matrix (ECM) debris. Evidence also suggests an important role of ISPs in the coordination of the inflammatory response. However, the effect of ISPs on inflammation is obfuscated by the confounding factors associated with cell death and inflammatory cell infiltration induced after cardiac injury. This study investigated whether neutrophil-derived cathepsin G (Cat.G) influences inflammation and remodeling in the absence of prior cardiac injury and cell death. METHODS AND RESULTS:Intracardiac catheter delivery of Cat.G (1 mg/kg) in rats induced significant left ventricular (LV) dilatation and cardiac contractile dysfunction at day 5, but not at day 2, post-delivery compared to vehicle-treated animals. Cat.G delivery also significantly increased matrix metalloprotease activity and collagen and fibronectin degradation at day 5 compared to vehicle-treated rats and these changes were associated with increased death signaling pathways and myocyte apoptosis. Mechanistic analysis shows that Cat.G-treatment induced potent chemotactic activity in hearts at day 2 and 5 post-delivery, characterized by processing and activation of interleukin (IL)-1β and IL-18, stimulation of inflammatory signaling pathways and accumulation of myeloid cells when compared to vehicle-treated rats. Cat.G-induced processing of IL-1β and IL-18 was independent of the canonical NLRP-3 inflammasome pathway and treatment of isolated cardiomyocytes with inhibitors of NLRP-3 or caspase-1 failed to reduce Cat.G-induced cardiomyocyte death. Notably, rats treated with IL-1 receptor antagonist (IL-1Ra) show reduced inflammation and improved cardiac remodeling and function following Cat.G delivery. CONCLUSIONS:Cat.G exerts potent chemoattractant and pro-inflammatory effects in non-stressed or injured heart in part through processing and activation of IL-1 family cytokines, subsequently leading to adverse cardiac remodeling and function. Thus, targeting ISPs could be a novel therapeutic strategy to reduce cardiac inflammation and improve cardiac remodeling and function after injury or stress.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Miller SA,Kolpakov MA,Guo X,Du B,Nguyen Y,Wang T,Powel P,Dell'Italia LJ,Sabri Adoi
10.1016/j.yjmcc.2019.06.016subject
Has Abstractpub_date
2019-09-01 00:00:00pages
29-39eissn
0022-2828issn
1095-8584pii
S0022-2828(19)30136-1journal_volume
134pub_type
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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doi:10.1016/j.yjmcc.2006.02.007
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/s0022-2828(84)80624-0
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journal_title:Journal of molecular and cellular cardiology
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doi:10.1016/s0022-2828(88)80014-2
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doi:10.1016/j.yjmcc.2010.10.011
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journal_title:Journal of molecular and cellular cardiology
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doi:10.1016/j.yjmcc.2003.11.008
更新日期:2004-02-01 00:00:00
abstract::Duchenne Muscular Dystrophy (DMD) cardiomyopathy is a progressive lethal disease caused by the lack of the dystrophin protein in the heart. The most widely used animal model of DMD is the dystrophin-deficient mdx mouse; however, these mice exhibit a mild dystrophic phenotype with heart failure only late in life. In co...
journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1016/j.yjmcc.2017.06.004
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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abstract::Heart failure is associated with mitochondrial dysfunction so that restoring or improving mitochondrial health is of therapeutic importance. Recently, reduction in NAD+ levels and NAD+-mediated deacetylase activity has been recognized as negative regulators of mitochondrial function. Using a cardiac specific KLF4 defi...
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doi:10.1016/j.yjmcc.2017.09.001
更新日期:2017-11-01 00:00:00
abstract::During lipid oversupply, the heart becomes insulin resistant, as exemplified by defective insulin-stimulated glucose uptake, and will develop diastolic dysfunction. In the healthy heart, not only insulin, but also increased contractile activity stimulates glucose uptake. Upon increased contraction both AMP-activated p...
journal_title:Journal of molecular and cellular cardiology
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