Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Endothelial Function

Background:

• Heart failure with preserved ejection fraction (HFpEF) is linked to endothelial dysfunction.
• Statins have previously shown potential in preventing endothelial dysfunction by inhibiting microRNA-133a (miR-133a).

Purpose of the Study:

• To investigate the effects of statins on HFpEF.
• To elucidate the underlying molecular mechanisms of statin action in HFpEF.

Main Methods:

• Investigated statin effects on circRNA-RBCK1 expression and AP-2α activity in endothelial cells.
• Examined the interaction between circRNA-RBCK1 and miR-133a.
• Utilized in vivo mouse models of HFpEF to assess lovastatin's impact on diastolic function, including experiments with endothelial AP-2α and circRNA-RBCK1 loss-of-function.

Main Results:

• Statins upregulate circular RNA-RBCK1 (circRNA-RBCK1) expression, co-transcribed with the RBCK1 gene.
• Statins enhance activator protein 2 alpha (AP-2α) transcriptional activity, promoting circRNA-RBCK1 interaction with miR-133a.
• AP-2α directly binds to the RBCK1 gene promoter in endothelial cells.
• Lovastatin improved diastolic function in HFpEF mice, an effect abrogated by endothelial AP-2α or circRNA-RBCK1 deficiency.

Conclusions:

• Statins activate the AP-2α/circRNA-RBCK1 pathway in cardiac endothelial cells.
• This signaling cascade suppresses miR-133a, thereby preventing diastolic dysfunction in HFpEF.
• The findings highlight a novel mechanism for statin-mediated cardioprotection in HFpEF.