UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension

Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling prote...

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Autores principales:	Xu Chen, Sadia Ashraf, Nadia Ashraf, Romain Harmancey
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	diastolic function hypertension obesity oxidative stress uncoupling protein Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/b5bc884bbb724a47adda4317bfa51c2f
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spelling	oai:doaj.org-article:b5bc884bbb724a47adda4317bfa51c2f2021-11-23T11:36:35ZUCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension10.1161/JAHA.121.0225562047-9980https://doaj.org/article/b5bc884bbb724a47adda4317bfa51c2f2021-09-01T00:00:00Zhttps://www.ahajournals.org/doi/10.1161/JAHA.121.022556https://doaj.org/toc/2047-9980Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3+/‐) to test the hypothesis that decreased UCP3 promotes left ventricular diastolic dysfunction during hypertension. Methods and Results Ucp3+/‐ rats and ucp3+/+ littermates fed a high‐salt diet (HS; 2% NaCl) and treated with angiotensin II (190 ng/kg per min for 28 days) experienced a similar rise in blood pressure (158±4 versus 155±7 mm Hg). However, UCP3 insufficiency worsened diastolic dysfunction according to echocardiographic assessment of left ventricular filling pressures (E/e’; 18.8±1.0 versus 14.9±0.6; P<0.05) and the isovolumic relaxation time (24.7±0.6 versus 21.3±0.5 ms; P<0.05), as well as invasive monitoring of the diastolic time constant (Tau; 15.5±0.8 versus 12.7±0.2 ms; P<0.05). Exercise tolerance on a treadmill also decreased for HS/angiotensin II‐treated ucp3+/‐ rats. Histological and molecular analyses further revealed that UCP3 insufficiency accelerated left ventricular concentric remodeling, detrimental interstitial matrix remodeling, and fetal gene reprogramming during hypertension. Moreover, UCP3 insufficiency increased oxidative stress and led to greater impairment of protein kinase G signaling. Conclusions Our findings identified UCP3 insufficiency as a cause for increased incidence of left ventricular diastolic dysfunction during hypertension. The results add further support to the use of antioxidants targeting mitochondrial reactive oxygen species as an adjuvant therapy for preventing heart failure with preserved ejection fraction in individuals with obesity.Xu ChenSadia AshrafNadia AshrafRomain HarmanceyWileyarticlediastolic functionhypertensionobesityoxidative stressuncoupling proteinDiseases of the circulatory (Cardiovascular) systemRC666-701ENJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 10, Iss 18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	diastolic function hypertension obesity oxidative stress uncoupling protein Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	diastolic function hypertension obesity oxidative stress uncoupling protein Diseases of the circulatory (Cardiovascular) system RC666-701 Xu Chen Sadia Ashraf Nadia Ashraf Romain Harmancey UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension
description	Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3+/‐) to test the hypothesis that decreased UCP3 promotes left ventricular diastolic dysfunction during hypertension. Methods and Results Ucp3+/‐ rats and ucp3+/+ littermates fed a high‐salt diet (HS; 2% NaCl) and treated with angiotensin II (190 ng/kg per min for 28 days) experienced a similar rise in blood pressure (158±4 versus 155±7 mm Hg). However, UCP3 insufficiency worsened diastolic dysfunction according to echocardiographic assessment of left ventricular filling pressures (E/e’; 18.8±1.0 versus 14.9±0.6; P<0.05) and the isovolumic relaxation time (24.7±0.6 versus 21.3±0.5 ms; P<0.05), as well as invasive monitoring of the diastolic time constant (Tau; 15.5±0.8 versus 12.7±0.2 ms; P<0.05). Exercise tolerance on a treadmill also decreased for HS/angiotensin II‐treated ucp3+/‐ rats. Histological and molecular analyses further revealed that UCP3 insufficiency accelerated left ventricular concentric remodeling, detrimental interstitial matrix remodeling, and fetal gene reprogramming during hypertension. Moreover, UCP3 insufficiency increased oxidative stress and led to greater impairment of protein kinase G signaling. Conclusions Our findings identified UCP3 insufficiency as a cause for increased incidence of left ventricular diastolic dysfunction during hypertension. The results add further support to the use of antioxidants targeting mitochondrial reactive oxygen species as an adjuvant therapy for preventing heart failure with preserved ejection fraction in individuals with obesity.
format	article
author	Xu Chen Sadia Ashraf Nadia Ashraf Romain Harmancey
author_facet	Xu Chen Sadia Ashraf Nadia Ashraf Romain Harmancey
author_sort	Xu Chen
title	UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension
title_short	UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension
title_full	UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension
title_fullStr	UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension
title_full_unstemmed	UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension
title_sort	ucp3 (uncoupling protein 3) insufficiency exacerbates left ventricular diastolic dysfunction during angiotensin ii‐induced hypertension
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/b5bc884bbb724a47adda4317bfa51c2f
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UCP3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin II‐Induced Hypertension

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