Drp1 knockdown aggravates obesity-induced cardiac dysfunction and remodeling

Area of Science:

• Cardiovascular Biology
• Mitochondrial Dynamics
• Metabolic Disease

Background:

• Obesity is a significant risk factor for heart failure with preserved ejection fraction (HFpEF).
• Dynamin related protein 1 (Drp1) regulates mitochondrial health, but its role in obesity-related HFpEF is unclear.

Purpose of the Study:

• To investigate the role of endogenous Drp1 in the development of obesity-induced HFpEF.
• To understand how Drp1 deficiency impacts cardiac function and mitochondrial dynamics under metabolic stress.

Main Methods:

• Generated heart-specific heterozygous Drp1 knockout (hetCKO) mice using αMHC-MerCreMer and tamoxifen induction.
• Administered an 18-week high-fat diet (HFD) to control and hetCKO mice.
• Assessed cardiac function, metabolic parameters, mitochondrial morphology, mitophagy, apoptosis, and inflammation.

Main Results:

• HFD induced similar weight gain and insulin resistance in both groups, but exacerbated diastolic dysfunction, fibrosis, cell death, and inflammation in hetCKO hearts.
• Drp1 deficiency blocked HFD-induced mitochondrial fission but worsened energy deficiency, suppressed mitophagy, and increased apoptosis and oxidative stress.
• These findings indicate aggravated cardiac remodeling and diastolic dysfunction in hetCKO mice under HFD conditions.

Conclusions:

• Endogenous Drp1 plays a protective role in mitigating metabolic stress-induced heart dysfunction.
• Drp1 regulates mitophagy, oxidative stress, mitochondrial function, apoptosis, and inflammation, thereby limiting HFpEF progression.
• Targeting Drp1 may offer therapeutic potential for metabolic stress-induced HFpEF.