Reduced cardiac antioxidant defenses mediate increased susceptibility to workload-induced myocardial injury in males with genetic cardiomyopathy
Copyright © 2024 Elsevier Ltd. All rights reserved..
Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking β-sarcoglycan (β-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this β-SG-/- model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in β-SG-/- mice. Male β-SG-/- hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female β-SG-/- hearts. This protection of females was independent of ovarian hormones. Male β-SG-/- hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT1R) antagonism. Increasing general antioxidative defenses or increasing the levels of S-nitrosylation both provided protection to the hearts of β-SG-/- male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT1R-mediated amplification of workload-induced myocardial injury in male β-SG-/- mice. Improving oxidative defenses, specifically by increasing S-nitrosylation, provided protection to the male β-SG-/- heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:190 |
|---|---|
| Enthalten in: |
Journal of molecular and cellular cardiology - 190(2024) vom: 26. März, Seite 24-34 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Vetter, Tatyana A [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Angiotensin II type 1 receptor |
|---|
| Anmerkungen: |
Date Revised 30.03.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.1016/j.yjmcc.2024.03.004 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370172213 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370172213 | ||
| 003 | DE-627 | ||
| 005 | 20240331233900.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240327s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.yjmcc.2024.03.004 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1358.xml |
| 035 | |a (DE-627)NLM370172213 | ||
| 035 | |a (NLM)38527667 | ||
| 035 | |a (PII)S0022-2828(24)00044-0 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Vetter, Tatyana A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Reduced cardiac antioxidant defenses mediate increased susceptibility to workload-induced myocardial injury in males with genetic cardiomyopathy |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 30.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a Copyright © 2024 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking β-sarcoglycan (β-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this β-SG-/- model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in β-SG-/- mice. Male β-SG-/- hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female β-SG-/- hearts. This protection of females was independent of ovarian hormones. Male β-SG-/- hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT1R) antagonism. Increasing general antioxidative defenses or increasing the levels of S-nitrosylation both provided protection to the hearts of β-SG-/- male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT1R-mediated amplification of workload-induced myocardial injury in male β-SG-/- mice. Improving oxidative defenses, specifically by increasing S-nitrosylation, provided protection to the male β-SG-/- heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Angiotensin II type 1 receptor | |
| 650 | 4 | |a Antioxidant | |
| 650 | 4 | |a Dystrophic cardiomyopathy | |
| 650 | 4 | |a Myocardial injury | |
| 650 | 4 | |a S-nitrosylation | |
| 700 | 1 | |a Parthiban, Preethy |e verfasserin |4 aut | |
| 700 | 1 | |a Stevens, Jackie A |e verfasserin |4 aut | |
| 700 | 1 | |a Revelo, Xavier S |e verfasserin |4 aut | |
| 700 | 1 | |a Kohr, Mark J |e verfasserin |4 aut | |
| 700 | 1 | |a Townsend, DeWayne |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of molecular and cellular cardiology |d 1970 |g 190(2024) vom: 26. März, Seite 24-34 |w (DE-627)NLM00001964X |x 1095-8584 |7 nnns |
| 773 | 1 | 8 | |g volume:190 |g year:2024 |g day:26 |g month:03 |g pages:24-34 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.yjmcc.2024.03.004 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 190 |j 2024 |b 26 |c 03 |h 24-34 | ||