CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.
Lei ShiYanzhen TanWenying ZhengGuojie CaoHaitao ZhouPanpan LiJun CuiYujie SongLele FengHong LiWenju ShanBing ZhangWei YiPublished in: Cell death discovery (2024)
Pathological cardiac hypertrophy is an independent risk factor for heart failure. Disruption of mitochondrial protein homeostasis plays a key role in pathological cardiac hypertrophy; however, the mechanism of maintaining mitochondrial homeostasis in pathological cardiac hypertrophy remains unclear. In this study, we investigated the regulatory mechanisms of mitochondrial protein homeostasis in pathological cardiac hypertrophy. Wildtype (WT) mice, knockout mice, and mice transfected with lentivirus overexpressing mouse C1q-tumor necrosis factor-related protein-3 (CTRP3) underwent transverse aortic constriction or sham surgery. After 4 weeks, cardiac function, mitochondrial function, and oxidative stress injury were examined. For mechanistic studies, neonatal rat cardiomyocytes were treated with small interfering RNA or overexpression plasmids for the relevant genes. CTRP3 overexpression attenuated transverse aortic constriction (TAC) induced pathological cardiac hypertrophy, mitochondrial dysfunction, and oxidative stress injury compared to that in WT mice. TAC or Ang II resulted in compensatory activation of UPRmt, but this was not sufficient to counteract pathologic cardiac hypertrophy. CTRP3 overexpression further induced activation of UPRmt during pathologic cardiac hypertrophy and thereby alleviated pathologic cardiac hypertrophy, whereas CTRP3 knockout or knockdown inhibited UPRmt. ATF5 was a key regulatory molecule of UPRmt, as ATF5 knockout prevented the cardioprotective effect of CTRP3 in TAC mice. In vitro, SIRT1 was identified as a possible downstream CTRP3 effector molecule, and SIRT1 knockout blocked the cardioprotective effects of CTRP3. Our results also suggest that ATF5 may be regulated by SIRT1. Our study demonstrates that CTRP3 activates UPRmt via the SIRT1/ATF5 axis under pathological myocardial hypertrophy, thus attenuating mitochondrial dysfunction and oxidative stress injury.
Keyphrases
- oxidative stress
- diabetic rats
- transcription factor
- ischemia reperfusion injury
- dna damage
- endoplasmic reticulum stress
- induced apoptosis
- heart failure
- high fat diet induced
- left ventricular
- cell proliferation
- neoadjuvant chemotherapy
- wild type
- escherichia coli
- minimally invasive
- aortic valve
- neuropathic pain
- high glucose
- clinical trial
- coronary artery
- genome wide
- dendritic cells
- metabolic syndrome
- angiotensin ii
- dna methylation
- pulmonary artery
- locally advanced
- signaling pathway
- insulin resistance
- spinal cord
- type diabetes
- lymph node
- drug induced
- rectal cancer
- amino acid
- pulmonary arterial hypertension
- preterm birth
- single molecule