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Prelamin A mediates inflammation in dilated and HIV associated cardiomyopathies

Brayson, D; Frustaci, A; Verardo, R; Chimenti, C; Russo, MA; Hayward, R; Ahmad, SM; ... Shanahan, CM; + view all (2019) Prelamin A mediates inflammation in dilated and HIV associated cardiomyopathies. JCI Insight , 4 (22) , Article e126315. 10.1172/jci.insight.126315. Green open access

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Abstract

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues yet its impact upon the heart is unknown. Here we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy and show that a novel mouse model of cardiac specific prelamin A accumulation exhibited a phenotype consistent with ‘inflammatory cardiomyopathy’ which we observed to be similar to HIV associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings: (1) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (2) have implications for the management of HIV patients with cardiac disease suggesting protease inhibitors should be replaced with alternative therapies i.e. non-nucleoside reverse transcriptase inhibitors; and (3) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy.

Type: Article
Title: Prelamin A mediates inflammation in dilated and HIV associated cardiomyopathies
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/jci.insight.126315
Publisher version: https://doi.org/10.1172/jci.insight.126315
Language: English
Additional information: This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. https://creativecommons.org/licenses/by/4.0/
Keywords: Heart Failure, Cardiomyopathy, HIV, Prelamin A, Inflammation, Senescence
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10084379
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