Left Ventricular and Right Ventricular Hypertrophy Modelling to Study PAPP-A-Mediated IGFBP-4 Cleavage-a Mechanism...

Area of Science:

• Cardiovascular Research
• Molecular Cardiology
• Endocrinology

Background:

• Pathological cardiac hypertrophy, a precursor to heart failure, is characterized by abnormal enlargement of heart chambers.
• Right ventricular (RV) hypertrophy shows greater resistance compared to left ventricular (LV) hypertrophy.
• Insulin-like growth factors (IGFs) are crucial for cell growth and possess cardioprotective properties.

Purpose of the Study:

• To investigate the role of Pregnancy-associated plasma protein-A (PAPP-A) in regulating IGF bioavailability via IGF binding protein-4 (IGFBP-4) proteolysis in rat models of RV and LV hypertrophy.
• To explore potential differential mechanisms of IGF regulation between RVH and LVH.

Main Methods:

• Right ventricular hypertrophy (RVH) induced by monocrotaline and left ventricular hypertrophy (LVH) induced by the 1 Kidney 1 Clip (1K1C) model in rats.
• Assessment of cardiac chamber masses via heart morphometry and systolic blood pressure via tail-cuff plethysmography.
• Quantification of plasma B-type natriuretic peptide (BNP) and C-terminal IGFBP-4 (CT-IGFBP-4) using fluoroimmunoassay.

Main Results:

• Both RVH and LVH models were successfully established, showing significant increases in RV and LV masses, respectively.
• Plasma BNP levels were elevated in LVH, and hypertrophied cardiomyocytes secreted significantly more BNP in both RVH and LVH models.
• PAPP-A-mediated IGFBP-4 proteolysis was significantly elevated (4-fold) in RVH but remained unchanged in LVH compared to controls.

Conclusions:

• PAPP-A-driven IGFBP-4 proteolysis is predominantly elevated in RVH, suggesting differential IGF bioavailability between the ventricles.
• These findings highlight PAPP-A as a potential therapeutic target to enhance resistance to RV hypertrophy.
• The study elucidates a specific molecular mechanism contributing to the differing responses of the right and left ventricles to pathological stress.