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Cardiomyocyte CaM kinase II as a driver of cardiac inflammation and remodeling

心肌细胞 CaM 激酶 II 作为心脏炎症和重塑的驱动因素

基本信息

批准号：
10308392
负责人：
JOAN HELLER BROWN
金额：
$ 39.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308392
关键词：
Adult Anti-Inflammatory Agents Attenuated Biological Assay CCL2 gene Ca(2+)-Calmodulin Dependent Protein Kinase Cardiac Cardiac Myocytes Cause of Death Cells Development Failure Fibrosis Flow Cytometry Functional disorder Gene Deletion Gene Expression Generations Genetic Transcription Goals Growth Heart Heart Diseases Heart failure Hypertrophy Immune Immunohistochemistry In Situ Hybridization Inflammasome Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-1 Interleukin-18 Intervention Knock-out Knockout Mice Lead Mediating Mediator of activation protein Mus Muscle Cells Myocarditis Necrosis Phenotype Play Population Prevention Process Role Signal Transduction Signaling Molecule Site Stimulus Stress T-Lymphocyte Time Tissues Transgenic Mice Transgenic Organisms Ventricular Ventricular Dysfunction Work calmodulin-dependent protein kinase II cardiogenesis cell type chemokine cytokine immune activation knock-down macrophage novel p65 pressure prevent recruit response single-cell RNA sequencing

项目摘要

ABSTRACT The heart responds to stress through hypertrophic growth of cardiomyocytes and progresses to heart failure when stress is sustained. Our previous studies showed that hypertrophy in response to a variety of stimuli occurs independent of signaling through the calcium/calmodulin dependent protein kinase II (CaMKII) but that progression to heart failure is attenuated when CaMKII is deleted. Inflammation is a key contributor to the adverse remodeling associated with heart failure. The long term objective of this proposal is to demonstrate that CaMKII signaling within cardiomyocytes initiates cardiac inflammation in response to non-ischemic interventions such as pressure overload (TAC) and that this plays a significant role in the development of heart failure. Studies proposed in Aim 1 determine if cardiomyocyte localized CaMKII signaling drives cardiac inflammation using cardiac specific CaMKII knockout mice (CKO) to demonstrate loss of TAC-induced inflammatory gene expression and inflammasome activation. We determine if these responses occur specifically in cardiomyocytes by isolation of adult mouse ventricular myocytes from CTL and CKO mice, and by in situ hybridization and enzymatic assays in tissue sections. CaMKIIC transgenics and mice with cardiac specific KO of the p65 subunit of NFkB are used to further demonstrate involvement of the cardiomyocyte in igniting inflammation. Aim 2 asks whether cardiomyocyte CaMKII signaling contributes to accumulation of inflammatory/immune cells in response to TAC. Work in this aim uses CKO mice to demonstrate that TAC promotes immune cell responses through cardiomyocyte CaMKII initiated signals. Studies focus on macrophages and T-cells, using immunohistochemistry and flow cytometry as well as single cell RNA seq to comprehensively define specific populations of macrophages that accumulate in the heart. Cardiac specific KOs or knockdown of chemokines/cytokines is used to demonstrate that generation of these mediators in cardiomyocytes triggers responses of specific immune cell types. Aim 3 determines if blockade of cardiomyocyte CaMKII-initiated inflammation attenuates adverse remodeling and at what point this needs to be accomplished. Proposed studies use cardiac specific KO or inhibition of selected inflammatory mediators to demonstrate that their formation in cardiomyocytes is critical for development of fibrosis and ventricular dysfunction following TAC. Conditional gene deletion with AAV9 Cre is used to establish the time at which maximal benefit from CaMKII inhibition is achieved. Our findings should significantly impact future research since the cardiomyocyte has not previously been considered as a generator of inflammatory signals, the mechanisms by which inflammatory responses are activated in the absence of “alarmins” has not heretofore been determined, and the concept that most effective prevention of heart failure development could be achieved by early cardiomyocyte-targeted anti-inflammatory interventions is novel.

摘要

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular Signaling to Preserve Mitochondrial Integrity against Ischemic Stress in the Heart: Rescue or Remove Mitochondria in Danger.

DOI：
10.3390/cells10123330
发表时间：
2021-11-27
期刊：
Cells
影响因子：
6
作者：
Yu JD;Miyamoto S
通讯作者：
Miyamoto S

SiglecF(HI) Marks Late-Stage Neutrophils of the Infarcted Heart: A Single-Cell Transcriptomic Analysis of Neutrophil Diversification.

DOI：
10.1161/jaha.120.019019
发表时间：
2021-02-16
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Calcagno DM;Zhang C;Toomu A;Huang K;Ninh VK;Miyamoto S;Aguirre AD;Fu Z;Heller Brown J;King KR
通讯作者：
King KR

RhoA signaling increases mitophagy and protects cardiomyocytes against ischemia by stabilizing PINK1 protein and recruiting Parkin to mitochondria.

DOI：
10.1038/s41418-022-01032-w
发表时间：
2022-12
期刊：
CELL DEATH AND DIFFERENTIATION
影响因子：
12.4
作者：
Tu, MichelleZ;Tan, Valerie P.;Yu, Justin D.;Tripathi, Raghav;Bigham, Zahna;Barlow, Melissa;Smith, Jeffrey M.;Brown, Joan Heller;Miyamoto, Shigeki
通讯作者：
Miyamoto, Shigeki

The contribution of the cardiomyocyte to tissue inflammation in cardiomyopathies.

DOI：
10.1016/j.cophys.2020.10.003
发表时间：
2021-03
期刊：
Current opinion in physiology
影响因子：
2.5
作者：
Ninh VK;Brown JH
通讯作者：
Brown JH

A Kinase Interacting Protein 1 (AKIP1) promotes cardiomyocyte elongation and physiological cardiac remodelling.

DOI：
10.1038/s41598-023-30514-1
发表时间：
2023-03-10
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Nijholt, Kirsten T.;Sanchez-Aguilera, Pablo I.;Booij, Harmen G.;Oberdorf-Maass, Silke U.;Dokter, Martin M.;Wolters, Anouk H. G.;Giepmans, Ben N. G.;van Gilst, Wiek H.;Brown, Joan H.;de Boer, Rudolf A.;Sillje, Herman H. W.;Westenbrink, B. Daan
通讯作者：
Westenbrink, B. Daan