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A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging.

Abstract：

:Cardiac performance decreases with age, which is a major risk factor for cardiovascular disease and mortality in the aging human population, but the molecular mechanisms underlying cardiac aging are still poorly understood. Investigating the role of integrin-linked kinase (ilk) and β1-integrin (myospheroid, mys) in Drosophila, which colocalize near cardiomyocyte contacts and Z-bands, we find that reduced ilk or mys function prevents the typical changes of cardiac aging seen in wildtype, such as arrhythmias. In particular, the characteristic increase in cardiac arrhythmias with age is prevented in ilk and mys heterozygous flies with nearly identical genetic background, and they live longer, in line with previous findings in Caenorhabditis elegans for ilk and in Drosophila for mys. Consistent with these findings, we observed elevated β1-integrin protein levels in old compared with young wild-type flies, and cardiac-specific overexpression of mys in young flies causes aging-like heart dysfunction. Moreover, moderate cardiac-specific knockdown of integrin-linked kinase (ILK)/integrin pathway-associated genes also prevented the decline in cardiac performance with age. In contrast, strong cardiac knockdown of ilk or ILK-associated genes can severely compromise cardiac integrity, including cardiomyocyte adhesion and overall heart function. These data suggest that ilk/mys function is necessary for establishing and maintaining normal heart structure and function, and appropriate fine-tuning of this pathway can retard the age-dependent decline in cardiac performance and extend lifespan. Thus, ILK/integrin-associated signaling emerges as an important and conserved genetic mechanism in longevity, and as a new means to improve age-dependent cardiac performance, in addition to its vital role in maintaining cardiac integrity.

journal_name

Aging Cell

journal_title

Aging cell

authors

Nishimura M,Kumsta C,Kaushik G,Diop SB,Ding Y,Bisharat-Kernizan J,Catan H,Cammarato A,Ross RS,Engler AJ,Bodmer R,Hansen M,Ocorr K

doi

10.1111/acel.12193

subject

Has Abstract

pub_date

2014-06-01 00:00:00

pages

431-40

issue

eissn

1474-9718

issn

1474-9726

journal_volume

pub_type

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A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging.