Mitochondrial oxidative stress contributes to diastolic dysfunction through impaired mitochondrial dynamics

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Pathophysiology

Background:

• Diastolic dysfunction (DD) is a key feature of heart failure with preserved ejection fraction (HFpEF), a growing clinical syndrome linked to aging.
• Current treatments for HFpEF are limited, and the molecular mechanisms of redox-sensitive cardiac remodeling in DD are not fully understood.
• Oxidative stress is implicated in DD, but its specific role and pathways remain under investigation.

Purpose of the Study:

• To investigate the role of NOX4-dependent mitochondrial oxidative stress in the development of DD.
• To elucidate the molecular mechanisms linking mitochondrial dysfunction, fibrosis, and DD.
• To evaluate the therapeutic potential of NOX inhibition and antioxidant strategies in DD.

Main Methods:

• Utilized transgenic mice overexpressing mitochondria-targeted NOX4 (Nox4TG618) as a model of DD.
• Assessed cardiac function using echocardiography and invasive hemodynamic measurements.
• Analyzed mitochondrial function, dynamics, apoptosis, inflammatory markers, extracellular matrix (ECM) deposition, and cardiomyocyte structure.
• Examined cardiac samples from patients with DD for similar pathological changes.
• Tested the efficacy of a NOX inhibitor (GKT137831) and mCAT overexpression in preventing DD.

Main Results:

• Nox4TG618 mice exhibited DD with preserved ejection fraction, characterized by mitochondrial fragmentation, impaired mitochondrial respiration and dynamics, increased apoptosis, and elevated pro-fibrotic and pro-inflammatory markers (TGFβ, osteopontin, MCP-1).
• Increased ECM deposition, interstitial fibrosis (collagen I), altered cardiomyocyte calcium handling (increased I_CaL), and Z-disc disruption were observed in Nox4TG618 mice.
• Pathological changes in Nox4TG618 mice mirrored those found in human DD patient samples.
• Treatment with GKT137831 or mCAT overexpression attenuated myocardial fibrosis and prevented DD in the model.

Conclusions:

• Mitochondrial oxidative stress driven by NOX4 is a significant contributor to DD.
• The study elucidates key mechanisms including mitochondrial dysfunction, impaired dynamics, fibrosis, and altered cardiomyocyte calcium handling.
• Targeting NOX enzymes or enhancing antioxidant defenses shows promise for treating DD and HFpEF.