Targeting CaMKII-δ9 Ameliorates Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Inflammation

Circulation Research, Journal Year: 2022, Volume and Issue: 130(6), P. 887 - 903

Published: Feb. 14, 2022

Background: CaMKII (Ca 2+ /calmodulin-dependent kinase II) plays a central role in cardiac ischemia/reperfusion (I/R) injury—an important therapeutic target for ischemic heart disease. In the heart, CaMKII-δ is predominant isoform and further alternatively spliced into 11 variants. humans, CaMKII-δ9 CaMKII-δ3, major splice variants, inversely regulate cardiomyocyte viability with former pro-death latter pro-survival. However, it unknown whether specific inhibition of detrimental prevents I/R injury and, if so, what underlying mechanism. Here, we aim to investigate cardioprotective effect against myocardial damage determine mechanisms. Methods: The mechanism were investigated mice vivo, neonatal rat ventricular myocytes, human embryonic stem cell–derived cardiomyocytes. Results: We demonstrate that knockdown or knockout its feature exon, exon 16, protects I/R-elicited subsequent failure. I/R-induced inflammation was also ameliorated by inhibition, compared previously well-studied CaMKII-δ2, overexpression caused more profound inflammation. Mechanistically, addition IKKβ (inhibitor NF-κB [nuclear factor-κB] subunit β), CaMKII-δ9, but not δ2, directly interacted IκBα (NF-κB inhibitor α) 13-16-17 combination increased phosphorylation consequently elicited pronounced activation signaling inflammatory response. Furthermore, essential confirmed Conclusions: only identified CaMKII-δ9-IKK/IκB-NF-κB as new regulator demonstrated specifically targeting most abundant variant markedly suppresses activation, inflammation, subsequently ameliorates remodeling failure, providing novel strategy various diseases.

Language: Английский

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CaMKII as a Therapeutic Target in Cardiovascular Disease

The Annual Review of Pharmacology and Toxicology, Journal Year: 2022, Volume and Issue: 63(1), P. 249 - 272

Published: Aug. 17, 2022

CaMKII (the multifunctional Ca

Language: Английский

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The role of inflammasomes in human diseases and their potential as therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 5, 2024

Abstract Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three components: an upstream sensor molecule is connected to downstream effector such as caspase-1 through adapter ASC. Inflammasome formation typically occurs response infectious agents or cellular damage. The active then triggers activation, followed by secretion of pro-inflammatory cytokines pyroptotic cell death. Aberrant activation activity contribute development diabetes, cancer, several cardiovascular neurodegenerative disorders. As result, recent research increasingly focused on investigating mechanisms regulate assembly well potential targeting inflammasomes treat various diseases. Multiple clinical trials currently underway evaluate therapeutic distinct inflammasome-targeting therapies. Therefore, understanding how different disease pathology may have significant implications for developing novel strategies. In this article, we provide summary biological pathological roles health disease. We also highlight key evidence suggests could be strategy new disease-modifying therapies effective conditions.

Language: Английский

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Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 31, 2024

Abstract The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate system, macrophages play an essential initial inflammatory that occurs following injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, diverse phenotypes and phenotypic alterations strongly associate with distinct types severity diseases, including coronary heart disease, valvular myocarditis, cardiomyopathy, failure, atherosclerosis aneurysm, which underscores importance investigating macrophage regulatory mechanisms within context specific diseases. Besides, recent strides single-cell sequencing technologies have revealed heterogeneity, cell–cell interactions, downstream therapeutic targets at higher resolution, brings new perspectives into macrophage-mediated potential Remarkably, myocardial fibrosis, prevalent characteristic most cardiac remains formidable clinical challenge, necessitating profound investigation impact on fibrosis In this review, we systematically summarize functional plasticity diseases unprecedented insights introduced by technologies, focus different causes characteristics especially relationship between inflammation (myocardial infarction, pressure overload, dilated diabetic cardiomyopathy aging) vascular injury (atherosclerosis aneurysm). Finally, highlight preclinical/clinical targeting strategies translational implications.

Language: Английский

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Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR‐141‐mediated NLRP3 inflammasome and TGF‐β1/Smads signaling in diabetic cardiomyopathy

The FASEB Journal, Journal Year: 2020, Volume and Issue: 34(4), P. 5282 - 5298

Published: Feb. 17, 2020

Melatonin is a hormone produced by the pineal gland, and it has extensive beneficial effects on various tissue organs; however, whether melatonin any effect cardiac fibrosis in pathogenesis of diabetic cardiomyopathy (DCM) still unknown. Herein, we found that administration significantly ameliorated dysfunction reduced collagen production inhibiting TGF-β1/Smads signaling NLRP3 inflammasome activation, as manifested downregulating expression TGF-β1, p-Smad2, p-Smad3, NLRP3, ASC, cleaved caspase-1, mature IL-1β, IL-18 heart melatonin-treated mice with diabetes mellitus (DM). Similar were consistently observed high glucose (HG)-treated fibroblasts (CFs). Moreover, also lncRNA MALAT1 (lncR-MALAT1) was increased along concomitant decrease microRNA-141 (miR-141) DM HG-treated CFs. Furthermore, established TGF-β1 target genes miR-141 lncR-MALAT1 an endogenous sponge or ceRNA to limit functional availability miR-141. Finally, knockdown abrogated anti-fibrosis action Our findings indicate produces antifibrotic via lncR-MALAT1/miR-141-mediated activation signaling, might be considered potential agent for treatment DCM.

Language: Английский

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