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
| Title | Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies |
|---|---|
| Type | Journal article |
| Authors | 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. |
| 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 number | e126315 |
| Journal | JCI Insight |
| Journal citation | 4 (22) |
| ISSN | 2379-3708 |
| Year | 2019 |
| Publisher | American 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 | |
| Published | 17 Oct 2019 |