RESUMO
Alström syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. The latter are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and poorly understood. We assessed cardiac function of Alms1 knockout (KO) mice by echocardiography. Cardiac function was unaltered in Alms1 global KO mice of both sexes at postnatal day 15 (P15) and 8â weeks. At 23â weeks, female - but not male - KO mice showed increased left atrial area and decreased isovolumic relaxation time, consistent with early restrictive cardiomyopathy, as well as reduced ejection fraction. No histological or transcriptional changes were seen in myocardium of 23-week-old female Alms1 global KO mice. Female mice with Pdgfra-Cre-driven Alms1 deletion in cardiac fibroblasts and in a small proportion of cardiomyocytes did not recapitulate the phenotype of global KO at 23â weeks. In conclusion, only female Alms1-deficient adult mice show echocardiographic evidence of cardiac dysfunction, consistent with the cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear but might involve metabolic or endocrine differences between sexes.
Assuntos
Síndrome de Alstrom , Cardiomiopatias , Ecocardiografia , Animais , Feminino , Masculino , Camundongos , Síndrome de Alstrom/complicações , Síndrome de Alstrom/genética , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/patologia , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Camundongos Knockout , Miocárdio/patologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenótipo , Caracteres SexuaisRESUMO
BACKGROUND: Cardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Noninvasive imaging using a radiotracer targeting these processes could be used to elucidate cardiac wound healing mechanisms. The alpha7 nicotinic acetylcholine receptor (É7nAChR) stimulates pro-reparative macrophage activity and angiogenesis, making it a potential imaging biomarker in this context. We investigated this by assessing in vitro cellular expression of É7nAChR, and by using a tritiated version of the PET radiotracer [18F]NS14490 in tissue autoradiography studies. RESULTS: É7nAChR expression in human monocyte-derived macrophages and vascular cells showed the highest relative expression was within macrophages, but only endothelial cells exhibited a proliferation and hypoxia-driven increase in expression. Using a mouse model of inflammatory angiogenesis following sponge implantation, specific binding of [3H]NS14490 increased from 3.6 ± 0.2 µCi/g at day 3 post-implantation to 4.9 ± 0.2 µCi/g at day 7 (n = 4, P < 0.01), followed by a reduction at days 14 and 21. This peak matched the onset of vessel formation, macrophage infiltration and sponge fibrovascular encapsulation. In a rat MI model, specific binding of [3H]NS14490 was low in sham and remote MI myocardium. Specific binding within the infarct increased from day 14 post-MI (33.8 ± 14.1 µCi/g, P ≤ 0.01 versus sham), peaking at day 28 (48.9 ± 5.1 µCi/g, P ≤ 0.0001 versus sham). Histological and proteomic profiling of É7nAChR positive tissue revealed strong associations between É7nAChR and extracellular matrix deposition, and rat cardiac fibroblasts expressed É7nAChR protein under normoxic and hypoxic conditions. CONCLUSION: É7nAChR is highly expressed in human macrophages and showed proliferation and hypoxia-driven expression in human endothelial cells. While NS14490 imaging displays a pattern that coincides with vessel formation, macrophage infiltration and fibrovascular encapsulation in the sponge model, this is not the case in the MI model where the É7nAChR imaging signal was strongly associated with extracellular matrix deposition which could be explained by É7nAChR expression in fibroblasts. Overall, these findings support the involvement of É7nAChR across several processes central to cardiac repair, with fibrosis most closely associated with É7nAChR following MI.