Local Hydrogel Release of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction

Eckhouse, Shaina R.; Purcell, Brendan P.; McGarvey, Jeremy R.; Lobb, David C; Logdon, Christina B; Doviak, Heather; O’Neill, Jason; Shuman, J.; Novack, Craig P; Zellars, Kia N.; Pettaway, Sara; Black, Roy A.; Khakoo, Aarif Y.; Lee, TaeWeon; Mukherjee, Rupak; Gorman, Joseph H.; Gorman, Robert C.; Burdick, Jason A.; Spinale, Francis G.

doi:10.1126/scitranslmed.3007244

Cited by 95 publications

(121 citation statements)

References 24 publications

(84 reference statements)

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“…Replenishment of TIMP4 in the ischemic myocardium shortly after the onset of reperfusion could minimize reperfusion-induced injury. Because prolonged presence of TIMP4 would be required for an effective recovery from reperfusion, TIMP4 delivery to the myocardium via viral overexpression, 47 or packaging in a biodegradable material to allow its slow release, 48 could serve as effective approaches. …”

Section: Discussionmentioning

confidence: 99%

Myocardial Recovery From Ischemia–Reperfusion Is Compromised in the Absence of Tissue Inhibitor of Metalloproteinase 4

Takawale

Fan

Basu

et al. 2014

Circ: Heart Failure

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Background-Myocardial reperfusion after ischemia (I/R), although an effective approach in rescuing the ischemic myocardium, can itself trigger several adverse effects including aberrant remodeling of the myocardium and its extracellular matrix. Tissue inhibitor of metalloproteinases (TIMPs) protect the extracellular matrix against excess degradation by matrix metalloproteinases (MMPs). TIMP4 levels are reduced in myocardial infarction; however, its causal role in progression of post-I/R injury has not been explored. Methods and Results-In vivo I/R (20-minute ischemia, 1-week reperfusion) resulted in more severe systolic and diastolic dysfunction in TIMP4 −/− mice with enhanced inflammation, oxidative stress (1 day post-I/R), hypertrophy, and interstitial fibrosis (1 week). After an initial increase in TIMP4 (1 day post-I/R), TIMP4 mRNA and protein decreased in the ischemic myocardium from wild-type mice by 1 week post-I/R and in tissue samples from patients with myocardial infarction, which correlated with enhanced activity of membrane-bound MMP, membrane-type 1 MMP. By 4 weeks post-I/R, wild-type mice showed no cardiac dysfunction, elevated TIMP4 levels (to baseline), and normalized membranetype 1 MMP activity. TIMP4-deficient mice, however, showed exacerbated diastolic dysfunction, sustained elevation of membrane-type 1 MMP activity, and worsened myocardial hypertrophy and fibrosis. Ex vivo I/R (20-or 30-minute ischemia, 45-minute reperfusion) resulted in comparable cardiac dysfunction in wild-type and TIMP4 −/− mice. Conclusions-TIMP4 is essential for recovery from myocardial I/R in vivo, primarily because of its membrane-type 1 MMP inhibitory function. TIMP4 deficiency does not increase susceptibility to ex vivo I/R injury. Replenishment of myocardial TIMP4 could serve as an effective therapy in post-I/R recovery for patients with reduced TIMP4. (Circ Heart Fail. 2014;7:652-662.)

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Section: Discussionmentioning

confidence: 99%

Myocardial Recovery From Ischemia–Reperfusion Is Compromised in the Absence of Tissue Inhibitor of Metalloproteinase 4

Takawale

Fan

Basu

et al. 2014

Circ: Heart Failure

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“…26, 27 Use of recombinant TIMPs may address these disadvantages. 16, 20 A potential concern for MMP inhibitors is that they may cause cardiac fibrosis. Studies have demonstrated that various MMP inhibitors increase the density of myofibroblasts that are responsible for cardiac fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction

Fan

et al. 2017

Biomacromolecules

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Following myocardial infarction (MI), degradation of extracellular matrix (ECM) by upregulated matrix metalloproteinases (MMPs) especially MMP-2 decreases tissue mechanical properties, leading to cardiac function deterioration. Attenuation of cardiac ECM degradation at the early stage of MI has the potential to preserve tissue mechanical properties, resulting in cardiac function increase. Yet the strategy for efficiently preventing cardiac ECM degradation remains to be established. Current preclinical approaches have shown limited efficacy due to low drug dosage allocated to the heart tissue, dose-limiting side effects, and cardiac fibrosis. To address these limitations, we have developed a MMP-2 inhibitor delivery system that can be specifically delivered into infarcted hearts at early stage of MI to efficiently prevent MMP-2-mediated ECM degradation. The system was based on an injectable, degradable, fast gelation and thermosensitive hydrogel, and a MMP-2 specific inhibitor, peptide CTTHWGFTLC (CTT). The use of fast gelation hydrogel allowed to completely retain CTT in the heart tissue. The system was able to release low molecular weight CTT over 4 weeks possibly due to the strong hydrogen bonding between the hydrogel and CTT. The release kinetics was modulated by amount of CTT loaded into the hydrogel, and using chondroitin sulfate and heparin that can interact with CTT and the hydrogel. Both glycosaminoglycans augmented CTT release while heparin more greatly accelerated the release. After injecting into the infarcted hearts for 4 weeks, the released CTT efficiently prevented cardiac ECM degradation as it not only increased tissue thickness, but also preserved collagen composition similar to that in the normal heart tissue. In addition, the delivery system significantly improved cardiac function. Importantly, the delivery system did not induce cardiac fibrosis. These results demonstrate that the developed MMP-2 inhibitor delivery system has potential to efficiently reduce adverse myocardial remodeling and improve cardiac function.

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“…During 14 days of observation, both infarct size and LV dilatation were reduced in the TIMP-3-treated pigs that also showed lower levels of inflammatory cytokines and increased smooth muscle actin content relative to the controls. 5 The continuous delivery of TIMP-3 obstructed post-MI remodeling in the animals treated with TIMP-3. Although TIMP-3 was effective at mitigating adverse MI effects in pigs, the fact that TIMP-4 is expressed in a narrow range of organs, and is the predominant TIMP in the heart, directs attention to this inhibitor for the treatment of cardiac disease.…”

Section: 15mentioning

confidence: 99%

“…4 Further, endogenous tissue inhibitors (TIMPs) that regulate the activities of MMPs in vivo, but have been generally dismissed as leads for developing clinical treatments, can be exogenously introduced to reduce adverse post-MI LV remodeling and inflammatory processes. 4,5 In addition, tetracycline, which was initially discovered as an antibacterial agent and used to develop a family of antibiotics and derivatives, also inhibits MMPs. In rodent hearts, doxycycline has a cardioprotective effect during reperfusion mediated by MMP-2 inhibition.…”

Section: Introductionmentioning

confidence: 99%

Hypothesis

Lizotte-Waniewski

Brew

Hennekens

2015

J Cardiovasc Pharmacol Ther

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The hypothesis that matrix metalloproteinase (MMP) inhibitors reduce risks of cardiovascular disease in humans is plausible, unproven, and difficult to test, due, in part, to differences in specificity and route of administration. Endogenous tissue inhibitors of metalloproteinases (TIMPs) are tight-binding, protein inhibitors that function in vivo and can be engineered to enhance specificity for desired targets. Nonetheless, TIMPs have been difficult to test, in part, because their secondary functions, including cell growth promotion and angiogenesis, raise concerns about side effects and they cannot be delivered orally. In contrast, doxycycline and other chemically modified tetracyclines are broad-spectrum, reversible MMP inhibitors with lower affinity but can be taken orally and have US Food and Drug Administration approval. The completed phase 2 randomized trials in humans of MMP inhibitors have methodologic limitations but generally show no significant benefits with adverse effects. At present, the principal research challenge is to achieve a better understanding of the complexities of biological functions of MMPs and subsequently to conduct large-scale phase 3 trials.

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Local Hydrogel Release of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction

Cited by 95 publications

References 24 publications

Myocardial Recovery From Ischemia–Reperfusion Is Compromised in the Absence of Tissue Inhibitor of Metalloproteinase 4

Myocardial Recovery From Ischemia–Reperfusion Is Compromised in the Absence of Tissue Inhibitor of Metalloproteinase 4

Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction

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