Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats

Area of Science:

• Neuroscience
• Cardiovascular Biology
• Molecular Medicine

Background:

• Tumor necrosis factor (TNF)-α converting enzyme (TACE) mediates inflammatory mediator shedding.
• TACE in the hypothalamic paraventricular nucleus (PVN) contributes to sympathetic excitation in heart failure (HF).

Purpose of the Study:

• To investigate if central TACE inhibition can reduce neuroinflammation and improve cardiac function in a rat model of HF.

Main Methods:

• Rats with myocardial infarction-induced HF or sham operations received PVN microinjection of TACE siRNA or ICV infusion of TACE inhibitor TAPI-0.
• Analyzed TACE levels, inflammatory markers (TNF-α, cyclooxygenase-2), and signaling pathways (NF-κB, ERK) in the PVN and cerebrospinal fluid.

Main Results:

• HF rats exhibited increased TACE, TNF-α, cyclooxygenase-2, p-NF-κB p65, and ERK1/2 in the PVN compared to SHAM rats.
• TACE siRNA and TAPI-0 treatment significantly attenuated these inflammatory markers and signaling molecules.
• Both interventions reduced sympathetic excitation, improved cardiac function, and decreased cardiac hypertrophy and fibrosis in HF rats.

Conclusions:

• Central TACE inhibition effectively mitigates neuroinflammation, sympathetic overactivation, and cardiac dysfunction in a rat model of HF.
• Targeting brain TACE activity presents a promising therapeutic approach for managing heart failure.