Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody

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 heartto-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 proinflammatory 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. , et al. (2020) Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody. PLoS ONE 15(4): e0231202. https://doi. 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. PLOS ONESpecific MMP9/2 antibody attenuates volume overload PLOS ONE | https://doi.org/10.

Molecular Changes in Prepubertal Left Ventricular Development Under Experimental Volume Overload

“…No difference between sexes was observed in any cardiac phenotype. These results confirmed that the LV VO was successfully established in ACF mice, consistent with previous publications ( 24 , 25 ).…”

“…In adult animals, ACF not only induces RV VO but also produces LV VO ( 24 , 25 ). In past studies, we demonstrated that ACF induces RV VO at neonatal and prepubertal animals ( 13 , 18 , 20 , 26 ), and VO induces different responses among neonatal, prepubertal, and adult RVs ( 13 , 26 , 27 ), highlighting the importance of developmental stage-specific analysis of the effect of VO on RV remodeling.…”

Prostaglandin-E2 receptor-4 stimulant rescues cardiac malfunction during myocarditis and protects the heart from adverse ventricular remodeling after myocarditis

“…Disruption of myocardial ECM via MMPs including MMP-2 and MMP-9 is a key trigger of adverse ventricular remodeling 20 – 23 , which is an important pathogenesis of DCM. To elucidate the molecular mechanisms underlying the development of DCM after myocarditis, we evaluated the expression and activation of MMP-2 and MMP-9 in the bulk heart tissues on day 56.…”

Extracellular Matrix in Cardiac Tissue Mechanics and Physiology: Role of Collagen Accumulation

“…Ruzicka et al reported an initial (within one week of induced volume overload) increase in elastin concentration but then a decrease of elastin concentration below control levels 10 weeks after induced volume overload [114]. The reduction of ECM turnover in volume overloaded LV was related to a phenotype change of fibroblasts into hypofibrotic type [116] and increased MMP expressions from macrophages or mast cells [117][118][119]. An increased collagen III/I ratio was also noted in the compensated stage of the remodeling [114].…”