p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction

Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understa...

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Main Authors: Xiaonan Chen, Hao Lin, Weiyao Xiong, Jianan Pan, Shuying Huang, Shan Xu, Shufang He, Ming Lei, Alex Chia Yu Chang, Huili Zhang
Format: Article
Jezik:English
Izdano: Wiley 2022-06-01
Serija:Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
Teme:
Online dostop:https://www.ahajournals.org/doi/10.1161/JAHA.121.024582
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author Xiaonan Chen
Hao Lin
Weiyao Xiong
Jianan Pan
Shuying Huang
Shan Xu
Shufang He
Ming Lei
Alex Chia Yu Chang
Huili Zhang
author_facet Xiaonan Chen
Hao Lin
Weiyao Xiong
Jianan Pan
Shuying Huang
Shan Xu
Shufang He
Ming Lei
Alex Chia Yu Chang
Huili Zhang
author_sort Xiaonan Chen
collection DOAJ
description Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. Methods and Results HFpEF dietary regimen (high‐fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second‐generation and third‐generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second‐generation telomerase RNA component knockout (at 6 weeks) and third‐generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial‐specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF. Conclusions Here we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride challenged murine model.
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spelling doaj.art-d889f51003894057ba781b51a8096bc42023-06-06T12:11:51ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-06-01111110.1161/JAHA.121.024582p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection FractionXiaonan Chen0Hao Lin1Weiyao Xiong2Jianan Pan3Shuying Huang4Shan Xu5Shufang He6Ming Lei7Alex Chia Yu Chang8Huili Zhang9Department of Cardiology Ninth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Cardiology Ninth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaShanghai Institute of Precision MedicineNinth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Cardiology Ninth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Cardiology Ninth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaShanghai Institute of Precision MedicineNinth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaShanghai Institute of Precision MedicineNinth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaShanghai Institute of Precision MedicineNinth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Cardiology Ninth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Cardiology Ninth People’s HospitalShanghai Jiao Tong University School of Medicine Shanghai ChinaBackground Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. Methods and Results HFpEF dietary regimen (high‐fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second‐generation and third‐generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second‐generation telomerase RNA component knockout (at 6 weeks) and third‐generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial‐specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF. Conclusions Here we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride challenged murine model.https://www.ahajournals.org/doi/10.1161/JAHA.121.024582agingHFpEFmitochondrial homeostasisp53 activation
spellingShingle Xiaonan Chen
Hao Lin
Weiyao Xiong
Jianan Pan
Shuying Huang
Shan Xu
Shufang He
Ming Lei
Alex Chia Yu Chang
Huili Zhang
p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
aging
HFpEF
mitochondrial homeostasis
p53 activation
title p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction
title_full p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction
title_fullStr p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction
title_full_unstemmed p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction
title_short p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction
title_sort p53 dependent mitochondrial compensation in heart failure with preserved ejection fraction
topic aging
HFpEF
mitochondrial homeostasis
p53 activation
url https://www.ahajournals.org/doi/10.1161/JAHA.121.024582
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