Electrical stimulation of cardiomyocytes activates mitochondrial matrix metalloproteinase causing electrical remodeling

Vacek, Thomas P.; Metreveli, Naira; Tyagi, Neetu; Vacek, Jonathan; Pagni, Sebastian; Tyagi, Suresh C.

doi:10.1016/j.bbrc.2010.12.039

Cited by 17 publications

(11 citation statements)

References 24 publications

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“…Cytochrome c leaks into the cytosol, and Bax translocates into the mitochondria ( 9 , 10 ). Data presented here show increased active MMP-9 in the mitochondria and its capillary cells in hyperglycemic conditions, and these results are in agreement with the results from others showing association of active mitochondrial MMP-9 with mechanical dysfunction of cardiac myocytes ( 27 ).…”

Section: Discussionsupporting

confidence: 93%

Abrogation of MMP-9 Gene Protects Against the Development of Retinopathy in Diabetic Mice by Preventing Mitochondrial Damage

et al. 2011

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OBJECTIVEIn the development of diabetic retinopathy, mitochondrial dysfunction is considered to play an important role in the apoptosis of retinal capillary cells. Diabetes activates matrix metalloproteinase-9 (MMP-9) in the retina and its capillary cells, and activated MMP-9 becomes proapoptotic. The objective of this study is to elucidate the plausible mechanism by which active MMP-9 contributes to the mitochondrial dysfunction in the retina.RESEARCH DESIGN AND METHODSUsing MMP-9 gene knockout (MMP-KO) mice, we investigated the effect of MMP-9 regulation on diabetes-induced increased retinal capillary cell apoptosis, development of retinopathy, mitochondrial dysfunction and ultrastructure, and mitochondrial DNA (mtDNA) damage. To understand how diabetes increases mitochondrial accumulation of MMP-9, interactions between MMP-9 and chaperone proteins (heat shock protein [Hsp] 70 and Hsp60) were evaluated. The results were confirmed in the retinal mitochondria from human donors with diabetic retinopathy, and in isolated retinal endothelial cells transfected with MMP-9 small interfering RNA (siRNA).RESULTSRetinal microvasculature of MMP-KO mice, diabetic for ∼7 months, did not show increased apoptosis and pathology characteristic of retinopathy. In the same MMP-KO diabetic mice, activation of MMP-9 and dysfunction of the mitochondria were prevented, and electron microscopy of the retinal microvasculature region revealed normal mitochondrial matrix and packed lamellar cristae. Damage to mtDNA was protected, and the binding of MMP-9 with Hsp70 or Hsp60 was also normal. As in the retina from wild-type diabetic mice, activation of mitochondrial MMP-9 and alterations in the binding of MMP-9 with chaperone proteins were also observed in the retina from donors with diabetic retinopathy. In endothelial cells transfected with MMP-9 siRNA, high glucose–induced damage to the mitochondria and the chaperone machinery was ameliorated.CONCLUSIONSRegulation of activated MMP-9 prevents retinal capillary cells from undergoing apoptosis by protecting mitochondrial ultrastructure and function and preventing mtDNA damage. Thus, MMP-9 inhibitors could have potential therapeutic value in preventing the development of diabetic retinopathy by preventing the continuation of the vicious cycle of mitochondrial damage.

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Section: Discussionsupporting

confidence: 93%

Abrogation of MMP-9 Gene Protects Against the Development of Retinopathy in Diabetic Mice by Preventing Mitochondrial Damage

et al. 2011

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“…Similar results were also observed in another cell-based therapy for dilated cardiomyopathy in a rat model (Sun et al 2009). Invitro studies also suggested that abnormal pacing or homocysteine treatment of isolated myocytes resulted in enhancement of mMMP-9 and myocyte dysfunction (Moshal et al 2009; Vacek et al 2011). Together, these studies suggest that abnormal mitochondrial biogenesis or enhanced oxidative stress in the mitochondria contribute to abnormal activation of MMP-9 and lead to degradation of important myocyte couplers such as Cx-43.…”

Section: Mitochondria In Heart Diseasementioning

confidence: 99%

Dysregulation of Mfn2 and Drp-1 proteins in heart failure

Givvimani

Pushpakumar

Veeranki

et al. 2014

Can. J. Physiol. Pharmacol.

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Therapeutic approaches for cardiac regenerative mechanisms have been explored over the past decade to target various cardiovascular diseases (CVD). Structural and functional aberrations of mitochondria have been observed in CVD. The significance of mitochondrial maturation and function in cardiomyocytes is distinguished by their attribution to embryonic stem cell differentiation into adult cardiomyocytes. An abnormal fission process has been implicated in heart failure, and treatment with mitochondrial division inhibitor 1 (Mdivi-1), a specific inhibitor of dynamin related protein-1 (Drp-1), has been shown to improve cardiac function. We recently observed that the ratio of mitofusin 2 (Mfn2; a fusion protein) and Drp-1 (a fission protein) was decreased during heart failure, suggesting increased mitophagy. Treatment with Mdivi-1 improved cardiac function by normalizing this ratio. Aberrant mitophagy and enhanced oxidative stress in the mitochondria contribute to abnormal activation of MMP-9, leading to degradation of the important gap junction protein connexin-43 (Cx-43) in the ventricular myocardium. Reduced Cx-43 levels were associated with increased fibrosis and ventricular dysfunction in heart failure. Treatment with Mdivi-1 restored MMP-9 and Cx-43 expression towards normal. In this review, we discuss mitochondrial dynamics, its relation to MMP-9 and Cx-43, and the therapeutic role of fission inhibition in heart failure.

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“…Electrical stimulation of cardiac cells was investigated by many research groups in both macro-and microscale (Cheng et al, 2006, Au al., 2007, Barash et al, 2010, Maidhof et al, 2012, Tandon et al, 2011, Vacek et al, 2011, Kujala et al, 2012, Boudou et al, 2012. Next to features such as culture medium perfusion, the presence of hemoglobin via oxygen carriers in the culture medium or the acting of cyclic stretch, electrical field stimulation is the most important to mimic heart tissue.…”

Section: Heart Tissue Culture and Toxicity Analysismentioning

confidence: 96%