Publications

2023

Santulli, Gaetano, Jessica Gambardella, Antonella Fiordelisi, Federica Andrea Cerasuolo, Xujun Wang, Nella Prevete, Eduardo Sommella, et al. (2023) 2023. “Infiltrating Macrophages Amplify Doxorubicin-Induced Cardiac Damage: Role of Catecholamines”. Cellular and Molecular Life Sciences : CMLS 80 (11): 323. https://doi.org/10.1007/s00018-023-04922-5.

BACKGROUND: The functional contribution of non-myocyte cardiac cells, such as inflammatory cells, in the setup of heart failure in response to doxorubicin (Dox) is recently becoming of growing interest.

OBJECTIVES: The study aims to evaluate the role of macrophages in cardiac damage elicited by Dox treatment.

METHODS: C57BL/6 mice were treated with one intraperitoneal injection of Dox (20 mg/kg) and followed up for 5 days by cardiac ultrasounds (CUS), histological, and flow cytometry evaluations. We also tested the impact of Dox in macrophage-depleted mice. Rat cardiomyoblasts were directly treated with Dox (D-Dox) or with a conditioned medium from cultured murine macrophages treated with Dox (M-Dox).

RESULTS: In response to Dox, macrophage infiltration preceded cardiac damage. Macrophage depletion prevents Dox-induced damage, suggesting a key role of these cells in promoting cardiotoxicity. To evaluate the crosstalk between macrophages and cardiac cells in response to DOX, we compared the effects of D-Dox and M-Dox in vitro. Cell vitality was lower in cardiomyoblasts and apoptosis was higher in response to M-Dox compared with D-Dox. These events were linked to p53-induced mitochondria morphology, function, and autophagy alterations. We identify a mechanistic role of catecholamines released by Dox-activated macrophages that lead to mitochondrial apoptosis of cardiac cells through β-AR stimulation.

CONCLUSIONS: Our data indicate that crosstalk between macrophages and cardiac cells participates in cardiac damage in response to Dox.

Santulli, Gaetano, Valentina Trimarco, Raffaele Izzo, Paola Gallo, Maria Virginia Manzi, Imma Forzano, Daniela Pacella, and Bruno Trimarco. (2023) 2023. “Long-Lasting Control of LDL-Cholesterol Induces a Forty Percent Reduction in the Incidence of Cardiovascular Events: New Insights from a 7-Year Study”. The Journal of Pharmacology and Experimental Therapeutics. https://doi.org/10.1124/jpet.123.001878.

Recent studies have yielded controversial results on the long-term effects of statin treatment on the risk of cardiovascular (CV) events. In order to fill this knowledge gap, we analyzed the relationship between LDL-C levels and CV events in hypertensive patients without previous CV events and naïve to antidyslipidemic treatment, within the "Campania Salute Network" in Southern Italy. We studied 725 hypertensive patients with a mean follow-up of 85.4{plus minus}25.7 months. We stratified our population into 3 groups based on LDL-Cholesterol (LDL-C) levels in mg/dL: Group 1) patients showing during the follow-up a mean LDL-C value {less than or equal to}100 mg/dL in absence of statin therapy; Group 2) statin-treated patients with LDL {less than or equal to}100 mg/dL; Group 3) patients with LDL-C >100 mg/dL, with or without statins. No significant difference among the groups was observed in terms of demographic and clinical characteristics and medications. The incidence of first CV events was 6.0% in Group 1, 5.7% in Group 2 (n.s. vs Group 1), and 11.9% in Group 3 (p<0.05 vs Group 1 and Group 2). A stable long-term satisfactory control of LDL-C plasma concentration ({less than or equal to}100 mg/dL) reduced the incidence of major CV events from 1 event every 58,6 patient/years to 1 event every 115,9 patient/years. These findings were confirmed in a Cox regression analysis, adjusting for potential confounding factors. Taken together, our data demonstrate that a 7-year stable control of LDL-C induces a forty percent reduction in the incidence of CV events. Significance Statement There are several discrepancies between Mendelian studies and other investigations on the actual effects of reduction of plasma concentration of LDL cholesterol on the incidence of major cardiovascular events. Taken together, our data in non-diabetic subjects show that a 7-year stable control of LDL cholesterol induces a  40% reduction in the incidence of cardiovascular events.