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

Daniel Brayson, Andrea Frustaci, Romina Verardo, Cristina Chimenti, Matteo Antonio Russo, Robert Hayward, Sadia Ahmad, Gema Vizcay-Barrena, Andrea Protti, Peter S. Zammit, Cristobal G. Dos Remedios, Elisabeth Ehler, Ajay M. Shah, Catherine M. Shanahan

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere126315
Pages (from-to)1-20
Number of pages20
JournalJCI insight
Volume4
Issue number22
DOIs
Publication statusPublished - Nov 14 2019

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Brayson, D., Frustaci, A., Verardo, R., Chimenti, C., Russo, M. A., Hayward, R., Ahmad, S., Vizcay-Barrena, G., Protti, A., Zammit, P. S., Dos Remedios, C. G., Ehler, E., Shah, A. M., & Shanahan, C. M. (2019). Prelamin A mediates myocardial inflammation in dilated and HIV-Associated cardiomyopathies. JCI insight, 4(22), 1-20. [e126315]. https://doi.org/10.1172/jci.insight.126315