Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies

Brayson, D., Frustaci, A., Verardo, R., Chimenti, C., Russo, M.A., Hayward, R., Ahmad, S.M., Vizcay-Barrena, G., Protti, A., Zammit, P.S., dos Remedios, C.G., Ehler, E., Shah, A.M. and Shanahan, C.M. 2019. Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies. JCI Insight. 4 (22) e126315. https://doi.org/10.1172/jci.insight.126315

TitlePrelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies
TypeJournal article
AuthorsBrayson, D., Frustaci, A., Verardo, R., Chimenti, C., Russo, M.A., Hayward, R., Ahmad, S.M., Vizcay-Barrena, G., Protti, A., Zammit, P.S., dos Remedios, C.G., Ehler, E., Shah, A.M. and Shanahan, C.M.
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 we show that a potentially 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 (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy.

Article numbere126315
JournalJCI Insight
Journal citation4 (22)
ISSN2379-3708
Year2019
PublisherAmerican Society for Clinical Investigation
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1172/jci.insight.126315
Web address (URL)https://doi.org/10.1172/jci.insight.126315
Publication dates
Published17 Oct 2019

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