Abstract
ObjectiveMonoclonal antibody derivatives are promising drugs for the treatment of various diseases due to their high matrix metalloproteinases (MMP) active site specificity. We studied the effects of a novel antibody, SDS3, which specifically recognizes the mature active site of MMP9/2 during ventricular remodeling progression in a mouse model of chronic volume overload (VO).MethodsVO was induced by creating an aortocaval fistula (ACF) in 10- to 12-week-old C57BL male mice. The VO-induced mice were treated with either vehicle control (PBS) or with SDS3 twice weekly by intraperitoneal (ip) injection. The relative changes in cardiac parameters between baseline (day 1) and end-point (day 30), were evaluated by echocardiography. The effects of SDS3 treatment on cardiac fibrosis, cardiomyocyte volume, and cardiac inflammation were tested by cardiac staining with Masson's trichrome, wheat Germ Agglutinin (WGA), and CD45, respectively. Serum levels of TNFα and IL-6 with and without SDS3 treatment were tested by ELISA.ResultsSDS3 significantly reduced cardiac dilatation, left ventricular (LV) mass, and cardiomyocyte hypertrophy compared to the vehicle treated animals. The antibody also reduced the heart-to-body weight ratio of the ACF animals to values comparable to those of the controls. Interestingly, the SDS3 group underwent significant reduction of cardiac inflammation and pro-inflammatory cytokine production, indicating a regulatory role for MMP9/2 in tissue remodeling, possibly by tumor necrosis factor alpha (TNFα) activation. In addition, significant changes in the expression of proteins related to mitochondrial function were observed in ACF animals, these changes were reversed following treatment with SDS3.ConclusionThe data suggest that MMP9/2 blockage with SDS3 attenuates myocardial remodeling associated with chronic VO by three potential pathways: downregulating the extracellular matrix proteolytic cleavage, reducing the cardiac inflammatory responses, and preserving the cardiac mitochondrial structure and function.
Highlights
Valvular heart diseases, congenital heart defects, and arteriovenous malformations lead to the development of sustained mechanical load in the heart
The data suggest that MMP9/2 blockage with SDS3 attenuates myocardial remodeling associated with chronic volume overload (VO) by three potential pathways: downregulating the extracellular matrix proteolytic cleavage, reducing the cardiac inflammatory responses, and preserving the cardiac mitochondrial structure and function
In order to assess the potential involvement of metalloproteinase activity and extracellular matrix (ECM) turnover, we induced a VO model in mice by means of an aortocaval fistula procedure
Summary
Congenital heart defects, and arteriovenous malformations lead to the development of sustained mechanical load (volume overload, VO) in the heart. Hearts subjected to this type of overload are challenged with the initiation of progressive left ventricular (LV) remodeling and dilatation, inflammatory cell infiltration, and extracellular matrix (ECM) degradation and reorganization, all of which eventually lead to heart failure with reduced ejection fraction (HFrEF) [1,2,3]. During the development of VO, LV dilatation is induced in a sustained manner and is associated with increased expression of pro-inflammatory cytokines and chemokines [13], as well as with partial collagen network disruption by matrix metalloproteinases (MMPs), which represent one of the major key enzymes in ECM turnover and remodeling [14, 15]. MMPs belong to a group of zinc-dependent enzymes that can be subdivided into several subgroups according to their substrate affinity profile, one of which is the gelatinase subgroup that includes MMP2 and MMP9
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