Methamphetamine induces cardiomyopathy through GATA4/NF-?B/SASP axis-mediated cellular senescence

With the world pandemic of methamphetamine (METH), METH-associated cardiomyopathy (MAC) has become a widespread epidemic and is also recognized as a cause of heart failure in young people. The mechanism of occurrence and development of MAC is not clear. In this study, firstly, the animal model was evaluated by echocardiography and myocardial pathological staining. The results revealed that the animal model exhibited cardiac injury consistent with clinical alterations of MAC, and the mice developed cardiac hypertrophy and fibrosis remodeling, which led to systolic dysfunction and left ventricular ejection fraction (%LVEF) < 40%. The expression of cellular senescence marker proteins (p16 and p21) and senescence-associated secretory phenotype (SASP) was significantly increased in mouse myocardial tissue. Secondly, mRNA sequencing analysis of cardiac tissues revealed the key molecule GATA4, and Western blot, qPCR and immunofluorescence results showed that the expression level of GATA4 was significantly increased after METH exposure. Finally, knockdown of GATA4 expression in H9C2 cells in vitro significantly attenuated METH-induced cardiomyocyte senescence. Conse-quently, METH causes cardiomyopathy through cellular senescence mediated by the GATA4/NF-kappa B/SASP axis, which is a feasible target for the treatment of MAC.

Automated summary

With the global prevalence of methamphetamine (METH), methamphetamine-associated cardiomyopathy (MAC) has become widespread, particularly among young people, leading to heart failure. The mechanism underlying MAC development remains unclear. In this study, an animal model exhibiting cardiac injury consistent with MAC was evaluated and found to display cardiac hypertrophy, fibrosis remodeling, and systolic dysfunction. The expression of cellular senescence markers (p16 and p21) and senescence-associated secretory phenotype (SASP) was significantly increased. Further analysis revealed that the key molecule GATA4 was upregulated in response to METH exposure. Knockdown of GATA4 expression in H9C2 cells attenuated METH-induced cardiomyocyte senescence. Therefore, METH induces cardiomyopathy through cellular senescence mediated by the GATA4/NF-kappa B/SASP axis, which presents a potential target for MAC treatment.