Potential Therapeutic Mechanism in Mice Model for Chronic Cardiac Volume Overload

Background: Chronic volume overload (VO) of the heart, leads to the ventricular dilatation and as a result to massive changes in the extracellular matrix (ECM). These changes are primarily dictated by the combined enzymatic activity of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinase (TIMPs).

Purpose: To explore the potential beneficial effects of a unique anti-MMP9/2 antibody(developed at the Weizmann Institute) on VO development and analyze the cellular and molecular mechanisms involved.

Methods:

1. Establishment of the mice model of VO - Aortocaval fistula (ACF).

2. Experimental groups: PBS-treated ACF mice and ACF mice treated with MMP9/2 antibody. Experimental duration: 4 weeks.

3. Cardiac functions were tested by echocardiography. Cardiac genes and proteins were tested by Real-Time PCR, Zymography and ELISA.

Results:Gross-anatomy demonstrated a visible cardiac hypertrophy in the ACF animals. Echocardiographic parameters showed consistent enlargement of left ventricle (LV) parameters in ACF animals compared to sham (LV end-diastolic area: 13.8±1 mm² to 16.1±0.8 mm², p<0.05, LV end-diastolic diameter: 4.2±0.1 mm to 4.7±0.1 mm, p<0.05) as well as LV mass (99.5±16 mg to 138±12 mg, p<0.05, respectively). Treatment with MMP9/2 antibody resulted in a reduction of LV area in the treated group compared to untreated group (37.9±6.6 % of change from end point to time 0 to 18.4±7 % of change from end point to time 0, p<0.05), as well as reduction of LV mass (62±6 % of change from end point to time 0 to 36 ±10 % of change from end point to time 0, p<0.05) Moreover, MMP9/2 antibody reduced the elevated secretion of TNFa observed in the ACF animals.

Conclusion: VO setting results in a marked elevation of MMP9/2 expression and activity in the heart. Blocking of the MMP-9/2 signaling attenuates VO-mediated cardiac dilatation, partially by reducing the ongoing inflammatory response.