MMP-2/TIMP-2/TIMP-4 versus MMP-9/TIMP-3 in transition from compensatory hypertrophy and angiogenesis to decompensatory heart failure^*

Abstract

Although matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) play vital role in tumor angiogenesis and TIMP-3 caused apoptosis, their role in cardiac angiogenesis is unknown. Interestingly, a disruption of coordinated cardiac hypertrophy and angiogenesis contributed to the transition to heart failure, however, the proteolytic and anti-angiogenic mechanisms of transition from compensatory hypertrophy to decompensatory heart failure were unclear. We hypothesized that after an aortic stenosis MMP-2 released angiogenic factors during compensatory hypertrophy and MMP-9/TIMP-3 released antiangiogenic factors causing decompensatory heart failure. To verify this hypothesis, wild type (WT) mice were studied 3 and 8 wks after aortic stenosis, created by banding the ascending aorta in WT and MMP-9−/− (MMP-9KO) mice. Cardiac function (echo, PV loops) was decreased at 8 wks after stenosis. The levels of MMP-2 (western blot) increased at 3 wks and returned to control level at 8 wks, MMP-9 increased only at 8 wks. TIMP-2 and −4 decreased at 3 and even more at 8 wks. The angiogenic VEGF increased at 3 wks and decreased at 8 wks, the antiangiogenic endostatin and angiostatin increased only at 8 wks. CD-31 positive endothelial cells were more intensely labeled at 3 wks than in sham operated or in 8 wks banded mice. Vascularization, as estimated by x-ray angiography, was increased at 3 wks and decreased at 8 wks post-banding. Although vast majority of studies were performed on control WT mice only, interestingly, MMP9-KO mice seemed to have increased vascular density 8 wks after banding. These results suggested that there was increase in MMP-2, decrease in TIMP-2 and −4, increase in angiogenic factors and vascularization in compensatory hearts. However, in decompensatory hearts there was increase in MMP-9, TIMP-3, endostatin, angiostatin and vascular rarefaction.

Tissue inhibitor of metalloproteinases-3 transfer suppresses malignant behaviors of colorectal cancer cells

“…TIMP3 is recognized as a multifunctional molecule in cell biology, covering cell differentiation, angiogenesis and immunology. 8,16,17 It has been reported that TIMP3 was involved in cancer apoptosis and invasion. In terms of the status of TIMP3 in cancer, it is also found downregulated in 95.2% clear renal cell carcinoma.…”

Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice

“…Accumulating evidence shows that MMPs and their physiological inhibitors, TIMPs, play a pivotal role in the cardiac remodeling progress (Spinale, 2007). It was recently reported that the transcriptional levels of MMP-2 were upregulated during the compensatory period and that the expression of MMP-9 was increased during the de-compensatory period (Givvimani et al, 2010). The loss or inhibition of MMP-9 suppresses the LV remodeling and dysfunction after acute pressure overload in mice (Heymans et al, 2005a).…”

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

“…Several MMPs are upregulated in cardiac hypertrophy and an imbalance between MMPs and their endogenous inhibitors (tissue inhibitor of metalloproteinases-TIMPs) may underlie the transition of compensated LVH to dilated LVH. [3][4][5][6][7] In addition, experimental evidence suggests that nonspecific inhibition of MMPs, especially MMP-2, ameliorates hypertensive cardiovascular remodelling. 8 MMPs activities are regulated at different levels including transcription, activation of latent forms of MMPs and inhibition by TIMPs 5,9 In this respect, genetic polymorphisms in MMP-2 gene may also affect MMP-2 expression or activity, as shown in several disease conditions.…”