Novel Role of Mitochondrial Matrix Metalloproteinase-2 in the Development of Diabetic Retinopathy

Mohammad, Ghulam; Kowluru, Renu A.

doi:10.1167/iovs.10-6368

Cited by 77 publications

(91 citation statements)

References 38 publications

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“…Studies have also demonstrated that retinal endothelial cell exposed to high glucose caused a profound increase in the expression of MMP-2 and -9 [45]. This is further supported by our previously published work from transgenic mice that are overexpressing the antioxidant enzyme superoxide dismutase (an antioxidant responsible for superoxide elimination) able to prevent the upregulation of MMP-2 in diabetic retina [36]. Transgenic MMP-9 Knockout mice showed enhanced retinal protection against oxidative stress and reduced apoptosis after diabetes.…”

Section: Mmps and Oxidative Stresssupporting

confidence: 59%

“…We, along with others, have shown that retinal cells incubated in high glucose upregulate the MMP-2 and -9 expression/activation, and inhibition of MMP-2 and -9 is able to prevent high glucose-induced retinal capillary cell apoptosis. Furthermore, we have also shown that high glucose translocate MMP-2 and -9 into the mitochondria and induce mitochondria dysfunction, and inhibition of MMP-2 and -9 ameliorate the high glucose-induced mitochondria dysfunction [23,24,26,35,36]. Hyperglycemia can lead to the activation of MMP-2 and -9 by oxidative stress, MAP kinase pathways [23,26,37].…”

mentioning

confidence: 83%

“…An active role of mitochondria dysfunction in the induction of apoptosis is well known, and it is postulated to play a major role in the development of diabetic retinopathy [36,64], but the mechanism which alters the mitochondria function and contributes in the development of retinopathy in diabetes is not clear. MMPs induction is considered as a negative regulator of cell survival in diabetes; latent MMPs are activated in the retina and its capillary cells, and activation of MMP-2 and -9 induces apoptosis of retinal capillary cells, a phenomenon that precedes the development of histopathology characteristic of retinopathy.…”

Section: Mmps and Mitochondria Dysfunctionmentioning

confidence: 99%

“…MMPs induction is considered as a negative regulator of cell survival in diabetes; latent MMPs are activated in the retina and its capillary cells, and activation of MMP-2 and -9 induces apoptosis of retinal capillary cells, a phenomenon that precedes the development of histopathology characteristic of retinopathy. Recent studies have shown that the damage of retinal mitochondria in diabetes is also mediated via MMPs, especially MMP-2 and -9, and over expression of the enzyme responsible for quenching mitochondrial superoxide, in addition to preventing diabetes-induced superoxide accumulation, inhibits MMPs activation and capillary cell apoptosis in retina of diabetic rodents [26,36,37]. Furthermore, under hyperglycemic condition, MMP-2 and -9 are activated in the mitochondria and elucidated as a causative link for mitochondria dysfunction [26,37].…”

Section: Mmps and Mitochondria Dysfunctionmentioning

confidence: 99%

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Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

Mohammad

Siddiquei

2012

j ocul biol dis inform

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Diabetic retinopathy represents the most common causes of vision loss in patients affected by diabetes mellitus. The cause of vision loss in diabetic retinopathy is complex and remains incompletely understood. One of the earliest changes in the development of retinopathy is the accelerated apoptosis of retinal microvascular cells and the formation of acellular capillaries by unknown mechanism. Results of a recent research suggest an important role of matrix metalloproteinases (MMPs) in the development of diabetic retinopathy. MMPs are a large family of proteinases that remodel extracellular matrix components, and under pathological condition, its induction is considered as a negative regulator of cell survival; and in diabetes, latent MMPs are activated in the retina and its capillary cells, and activation of MMP-2 and -9 induces apoptosis of retinal capillary cells. This review will focus on the MMP-2 and MMP-9 in the diabetic retina with special reference to oxidative stress, mitochondria dysfunction, inflammation and angiogenesis, as well as summarizing the current information linking these proteins to pathogenesis of diabetic retinopathy.

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Section: Mmps and Oxidative Stresssupporting

confidence: 59%

mentioning

confidence: 83%

Section: Mmps and Mitochondria Dysfunctionmentioning

confidence: 99%

Section: Mmps and Mitochondria Dysfunctionmentioning

confidence: 99%

See 2 more Smart Citations

Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

Mohammad

Siddiquei

2012

j ocul biol dis inform

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“…Positive controls consisting of retinal vessel exposed to DNAse before initiation of the TUNEL reaction were run simultaneously. After counting the number of TUNEL-positive capillary cells, the slides were stained with periodic acid-Schiff and hematoxylin for histologic evaluation, and the number of acellular capillaries was counted in multiple midretinal fields and expressed per square millimeter of retinal area examined [18,20,23].…”

Section: Gene Expressionmentioning

confidence: 99%

Interleukin-1β and mitochondria damage, and the development of diabetic retinopathy

Kowluru

Mohammad

Santos

et al. 2011

j ocul biol dis inform

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Mitochondrial dysfunction is considered to play an important role in the development of diabetic retinopathy. Recent evidence has also shown many similarities between diabetic retinopathy and a low grade chronic inflammatory disease. The aim of this study is to understand the interrelationship between proinflammtory mediator, IL-1β and mitochondrial dysfunction in the accelerated loss of capillary cells in the retina. Using IL-1β receptor gene knockout (IL-1R1 − / − ) diabetic mice, we have investigated the effect of regulation of IL-1β on mitochondrial dysfunction and mtDNA damage, and increased retinal capillary cell apoptosis and the development of retinopathy. Retinal mitochondrial dysfunction and mtDNA damage were significantly ameliorated in IL-1R1 − / − mice, diabetic for~10 months, compared to the wild-type diabetic mice. This was accompanied by protection of accelerated capillary cell apoptosis and the development of acellular capillaries, histopathology associated with diabetic retinopathy. Thus, mitochondrial damage could be one of the key events via which increased inflammation contributes to the activation of the apoptotic machinery resulting in the development of diabetic retinopathy, and the possible mechanism via which inflammation contributes to the development of diabetic retinopathy includes continuous fueling of the vicious cycle of mitochondrial damage, which could be disrupted by inhibitors of inflammatory mediators.

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Gap Junctions

Nielsen,

Nygaard Axelsen,

Sorgen

et al. 2012

Comprehensive Physiology

381

365

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Gap junctions are essential to the function of multicellular animals, which require a high degree of coordination between cells. In vertebrates, gap junctions comprise connexins and currently 21 connexins are known in humans. The functions of gap junctions are highly diverse and include exchange of metabolites and electrical signals between cells, as well as functions, which are apparently unrelated to intercellular communication. Given the diversity of gap junction physiology, regulation of gap junction activity is complex. The structure of the various connexins is known to some extent; and structural rearrangements and intramolecular interactions are important for regulation of channel function. Intercellular coupling is further regulated by the number and activity of channels present in gap junctional plaques. The number of connexins in cell‐cell channels is regulated by controlling transcription, translation, trafficking, and degradation; and all of these processes are under strict control. Once in the membrane, channel activity is determined by the conductive properties of the connexin involved, which can be regulated by voltage and chemical gating, as well as a large number of posttranslational modifications. The aim of the present article is to review our current knowledge on the structure, regulation, function, and pharmacology of gap junctions. This will be supported by examples of how different connexins and their regulation act in concert to achieve appropriate physiological control, and how disturbances of connexin function can lead to disease. © 2012 American Physiological Society. Compr Physiol 2:1981‐2035, 2012.

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Novel Role of Mitochondrial Matrix Metalloproteinase-2 in the Development of Diabetic Retinopathy

Abstract: Elevated MMP2 in the mitochondria degrades its membranes by modulating Hsp60 and damaging connexin 43, and this activates the apoptotic machinery. Better understanding of MMP2-mediated mitochondrial damage could help identify new strategies for the treatment of this blinding disease.

Cited by 77 publications

References 38 publications

Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

Interleukin-1β and mitochondria damage, and the development of diabetic retinopathy

Gap Junctions

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