Duration of ischaemia determines matrix metalloproteinase-2 activation in the reperfused rabbit heart

Prasan, Ananth M.; McCarron, Hugh C. K.; White, Melanie Y.; McLennan, Susan V.; Tchen, Adrian S.; Hambly, Brett D.; Jeremy, Richmond W.

doi:10.1002/1615-9861(200209)2:9<1204::aid-prot1204>3.0.co;2-k

Cited by 12 publications

(6 citation statements)

References 14 publications

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“…Other authors (Prasan et al 2002) showed that there is an increase in the pro‐MMP–2 activity after 60 min of low‐flow ischaemia. However, they used low‐flow ischaemia, which induced a permanent washout of the metabolites and enzymes, including MMP–2.…”

Section: Discussionmentioning

confidence: 95%

Role of matrix metalloproteinase‐2 in the cardioprotective effect of ischaemic postconditioning

Donato

D'Annunzio

Buchholz

et al. 2010

Experimental Physiology

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The activation of matrix metalloproteinases (MMPs) contributes to myocardial injury at the onset of reperfusion; however, their role in ischaemic postconditioning is unknown. The aim of the present study was to examine the effects of ischaemic postconditioning on MMP activity in isolated rabbit hearts. The isolated rabbit hearts were subjected to 30 min of global ischaemia followed by 180 min of reperfusion (I/R group; n = 8). In the ischaemic postconditioning group (n = 8), a postconditioning protocol was performed (2 cycles of 30 s reperfusion-ischaemia). In other experiments, we added doxycycline, an MMP inhibitor, at 25 (n = 7) or 50 μmol l −1 (n = 8) during the first 2 min of reperfusion. Coronary effluent and left ventricular tissue were collected during pre-ischaemic conditions and at different times during the reperfusion period to measure MMP-2 activity and cardiac protein nitration. We evaluated ventricular function and infarct size. In the I/R group, infarct size was 32.1 ± 5.2%; Postcon reduced infarct size to 9.5 ± 3.8% (P < 0.05) and inhibited MMP-2 activity during reperfusion. The administration of doxycycline at 50 μmol l −1 inhibited MMP-2 activity and cardiac protein nitration and reduced the infarct size to 9.7 ± 2.8% (P < 0.05). A lower dose of doxycycline (25 μmol l −1 ) failed to inhibit MMP-2 activity and did not modify the infarct size. Our results strongly suggest that ischaemic postconditioning may exert part of its cardioprotective effects through the inhibition of MMP-2 activity.

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Section: Discussionmentioning

confidence: 95%

Role of matrix metalloproteinase‐2 in the cardioprotective effect of ischaemic postconditioning

Donato

D'Annunzio

Buchholz

et al. 2010

Experimental Physiology

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“…A possible limitation of our study is the different perfusion times used in the protocols. Perfusion of the hearts could mildly alter oxidative stress itself, modifying the activity of MMP-2 in a time-dependent way (18). However, the activity data of MMP-2 were accompanied by changes in dystrophin levels, which significantly decreased during ischemia when MMP-2 activity was increased.…”

Section: Discussionmentioning

confidence: 99%

Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity

Opotowsky

Landzberg

Earing

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Impaired exercise capacity is common after the Fontan procedure and is attributed to cardiovascular limits. The Fontan circulation, however, is also distinctively vulnerable to unfavorable lung mechanics. This study aimed to define the prevalence and physiological relevance of pulmonary dysfunction in patients with Fontan physiology. We analyzed data from the Pediatric Heart Network Fontan Cross-Sectional Study to assess the prevalence and pattern of abnormal spirometry in Fontan patients (6-18 yr old) and investigated the relationship between low forced vital capacity (FVC) and maximum exercise variables, including peak O2 consumption (Vo2peak), among those who demonstrated adequate effort (n = 260). Average ages at the time of exercise testing and Fontan completion were 13.2 ± 3.0 and 3.5 ± 2.2 yr old, respectively. Aerobic capacity was reduced (Vo2peak: 67.3 ± 15.6% predicted). FVC averaged 79.0 ± 14.8% predicted, with 45.8% having a FVC less then the lower limit of normal. Only 7.8% demonstrated obstructive spirometry. Patients with low FVC had lower Vo2peak (64.4 ± 15.9% vs. 69.7 ± 14.9% predicted, P < 0.01); low FVC independently predicted lower Vo2peak after adjusting for relevant covariates. Among those with Vo2peak < 80% predicted (n = 204/260), 22.5% demonstrated a pulmonary mechanical contribution to exercise limitation (breathing reserve < 20%). Those with both low FVC and ventilatory inefficiency (minute ventilation/CO2 production > 40) had markedly reduced Vo2peak (61.5 ± 15.3% vs. 72.0 ± 14.9% predicted, P < 0.01) and a higher prevalence of pulmonary mechanical limit compared with patients with normal FVC and efficient ventilation (36.1% vs. 4.8%). In conclusion, abnormal FVC is common in young patients after the Fontan procedure and is independently associated with reduced exercise capacity. A large subset has a pathologically low breathing reserve, consistent with a pulmonary mechanical contribution to exercise limitation.

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“…MMP-2 is known to be transiently activated by acute myocardial injury [8,[18][19][20][21][22]. Pharmacological inhibition or targeted deletion of the MMP-2 gene attenuates left ventricular dilation and contractile depression early after murine myocardial infarction [18].…”

Section: Discussionmentioning

confidence: 99%

Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction

Zhou

Gray

et al. 2007

Biochemical and Biophysical Research Communications

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Matrix metalloproteinases (MMPs) are central to the development and progression of dysfunctional ventricular remodeling after tissue injury. We studied 6 month old heterozygous mice with cardiac-specific transgenic expression of active MMP-2 (MMP-2 Tg). MMP-2 Tg hearts showed no substantial gross alteration of cardiac phenotype compared to age-matched wild-type littermates. However, buffer perfused MMP-2 Tg hearts subjected to 30 min of global ischemia followed by 30 min of reperfusion had a larger infarct size and greater depression in contractile performance compared to wild-type hearts. Importantly, cardioprotection mediated by ischemic preconditioning (IPC) was completely abolished in MMP-2 Tg hearts, as shown by abnormalities in mitochondrial ultrastructure and impaired respiration, increased lipid peroxidation, cell necrosis and persistently reduced recovery of contractile performance during post-ischemic reperfusion. We conclude that MMP-2 functions not only as a proteolytic enzyme but also as a previously unrecognized active negative regulator of mitochondrial function during superimposed oxidative stress.

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Duration of ischaemia determines matrix metalloproteinase-2 activation in the reperfused rabbit heart

Cited by 12 publications

References 14 publications

Role of matrix metalloproteinase‐2 in the cardioprotective effect of ischaemic postconditioning

Role of matrix metalloproteinase‐2 in the cardioprotective effect of ischaemic postconditioning

Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity

Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction

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