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Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.
Xu, Man; Li, Li-Peng; He, Xi; Lu, Xing-Zhu; Bi, Xue-Yuan; Li, Qi; Xue, Xiao-Rong.
Afiliação
  • Xu M; Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University Affiliated People's Hospital, Xi'an, Shaanxi, China.
  • Li LP; Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University Affiliated People's Hospital, Xi'an, Shaanxi, China.
  • He X; Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
  • Lu XZ; Department of Pharmacy, Second Affiliated Hospital of Xi'an Jiaotong University Medical School, Xi'an, Shaanxi, China.
  • Bi XY; Department of Pharmacy, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • Li Q; Department of Science and Education, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University Affiliated People's Hospital, Xi'an, China.
  • Xue XR; Department of Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Northwest University Affiliated People's Hospital, Xi'an, Shaanxi, China.
FASEB J ; 38(9): e23654, 2024 May 15.
Article em En | MEDLINE | ID: mdl-38717442
ABSTRACT
Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Miócitos Cardíacos / Resposta a Proteínas não Dobradas / Fatores de Transcrição de Choque Térmico / Metformina Limite: Animals Idioma: En Revista: FASEB J Assunto da revista: BIOLOGIA / FISIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Miócitos Cardíacos / Resposta a Proteínas não Dobradas / Fatores de Transcrição de Choque Térmico / Metformina Limite: Animals Idioma: En Revista: FASEB J Assunto da revista: BIOLOGIA / FISIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China