Circulating matrix metalloproteinases and their endogenous inhibitors in patients with erectile dysfunction

Muniz, Jaqueline Jóice; Lacchini, Riccardo; Belo, Vanessa A.; Nobre, Y T D A; Tucci, Sílvio; Martins, Antônio Carlos Pereira; Tanus‐Santos, José Eduardo

doi:10.1038/ijir.2011.44

Cited by 11 publications

(9 citation statements)

References 35 publications

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“…Gelatin zymography of MMP-2 from LV and plasma samples was performed as previously described [30][31][32]. Briefly, tissues were homogenized in extraction buffer containing 10 mM CaCl 2 , 50 mM Tris-HCl, pH 7.4, 1 mM 1,10-phenanthroline, 1 mM phenylmethylsulfonyl fluoride (PMSF), 1 mM N-ethyl maleimide (NEM).…”

Section: Methodsmentioning

confidence: 99%

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

Ferraz

Sousa-Santos

Neto-Neves

et al. 2012

Basic Clin Pharma Tox

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Growing evidence supports the involvement of matrix metalloproteinases (MMPs) in the pathogenesis of many cardiovascular diseases. Particularly, imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling. While some studies have suggested that MMP-2 may affect the vascular tone and impair b-adrenoreceptor function, no previous study has examined the acute haemodynamic effects of MMP-2. We examined the effects of recombinant human MMP-2 (rhMMP-2) administered intravenously to anaesthetized lambs at baseline conditions and during b 1 -adrenergic cardiac stimulation with dobutamine. We used 26 anaesthetized male lambs in two study protocols. First, rhMMP-2 (220 ng/kg/min. over 60 min.) or vehicle was infused in the lambs, and no significant haemodynamic changes were found. Therefore, we infused dobutamine at 5 lg/kg/ min. i.v. (or saline) over 180 min. in lambs that had received the same rhMMP-2 infusion preceded by doxycycline i.v. at 10 mg/kg (or saline). Plasma and cardiac MMP-2 levels were assessed by gelatin zymography, and gelatinolytic activity was assessed by spectrofluorimetry. Dobutamine decreased systemic vascular resistance index, and this effect was attenuated by rhMMP-2 infusion. Moreover, dobutamine increased the cardiac index and left ventricular dP/dt max , and these effects were attenuated by rhMMP-2. The previous administration of doxycycline blunted rhMMP-2-induced changes in dobutamine responses. While the infusion of rhMMP-2 did not increase plasma and cardiac MMP-2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Our findings show that rhMMP-2 exerts no major haemodynamic effects in lambs. However, rhMMP-2 impairs the responses elicited by activation of b-adrenoreceptors.Growing evidence supports the involvement of a group of enzymes named matrix metalloproteinases (MMPs) in the pathogenesis of many disease conditions, including diseases affecting the cardiovascular system [1][2][3][4]. Particular attention has been paid to MMP-2 because imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling [5][6][7] and in other alterations of the cardiovascular system [8][9][10]. However, recent studies are clearly showing that MMP-2 may have many other targets unrelated to the extracellular matrix, including intracellular substrates [11,12] and other mediators possibly affecting the vascular tone such as bigendothelin-1[13], calcitonin gene-related peptide [14] and adrenomedullin [15]. Importantly, activated MMP-2 has been shown to impair cardiac function possibly as a result of its activity targeting sarcomeric and cytoskeletal proteins such as troponin I, myosin light chain-1, a-actinin and titin [16][17][18][19][20].Recent studies indicate that MMPs, including MMP-2, are involved in proteolytic cleavage of b 1 -and b 2 -adrenoreceptors [21]. Rodrigues et al. [22] demonstrated that the labelling density of the extracellular domain of b 2 -adrenergic receptor in aortic endothelial cells fro...

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Section: Methodsmentioning

confidence: 99%

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

Ferraz

Sousa-Santos

Neto-Neves

et al. 2012

Basic Clin Pharma Tox

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“…Circulating MMP are used as biomarkers in a variety of pathological conditions, including ED (Muniz et al 2012b). Our findings show that ethanol consumption increased MMP-9 levels without affecting its activity.…”

Section: R a F Tmentioning

confidence: 60%

“…MMP are regulated by TIMP (Nagase and Brew 2003), and disruption of the balance between MMP and their inhibition by TIMP may result in tissue remodeling (Brew and Nagase 2010). For this reason MMP/TIMP ratio is considered to be a better parameter to evaluate MMP actions than MMP expression/dosage (Muniz et al 2012b). We found that ethanol consumption did not change TIMP-1 and TIMP-2 expression in the rat CSM.…”

Section: R a F Tmentioning

confidence: 80%

Dysregulated mitogen-activated protein kinase and matrix metalloproteinase in ethanol-induced cavernosal dysfunction

Muniz

Leite

Lacchini

et al. 2018

Can. J. Physiol. Pharmacol.

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We evaluated the effects of ethanol consumption on the mitogen-activated protein kinases (MAPK) and metalloproteinases (MMP) pathways in the rat cavernosal smooth muscle (CSM). Male Wistar rats were treated with ethanol (20% v/v) for 6 weeks. Quantitative real-time polymerase chain reaction experiments showed that ethanol consumption did not alter mRNA levels of p38MAPK, SAPK/JNK, ERK1/2, MMP-2, or MMP-9 in the rat CSM. Western immunoblotting experiments revealed decreased protein expression of p38MAPK and phosphorylation of SAPK/JNK in the CSM from ethanol-treated rats. Additionally, ethanol consumption decreased the expression of MMP-2. Functional assays showed that SP600125, an inhibitor of SAPK/JNK, prevented the increase in endothelin (ET)-1-induced contraction in the CSM from ethanol-treated rats. Treatment with ethanol decreased MMP-2 activity, but did not change net MMP activity in the rat CSM. Ethanol consumption increased the circulating levels of MMP-2, MMP-9, and TIMP-2 as well as the MMP-9/TIMP-1 ratio. The major finding of our study is that ethanol consumption down-regulates both MAPK and MMP pathways in the rat CSM, whereas it increases the circulating levels of MMP-9. Additionally, we found that SAPK/JNK plays a role in ethanol-induced increase on ET-1 contraction in the isolated rat CSM.

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“…The production of extracellular matrix is most commonly recognized as an important pathological change in the corpus cavernosum of CNI-ED. Moreover, decreased net MMP activity was observed in patients with erectile dysfunction (Muniz et al, 2012), while intratunical injection of MSCs relieved penile fibrosis by stimulating the expression and activity of MMPs (Gokce et al, 2014). MMPs are capable of degrading all kinds of extracellular matrix proteins.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells and adipose-derived stem cells on erectile dysfunction in a rat model of bilateral cavernous nerve injury

Yang²,

Chen³

et al. 2022

Front. Bioeng. Biotechnol.

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Background: Cavernous nerve injury (CNI) is the leading cause of erectile dysfunction (ED) after radical prostatectomy and pelvic fracture. Transplantation of human adipose-derived stem cells (ASCs) has been widely used to restore erectile function in CNI-ED rats and patients. Umbilical cord blood-derived MSCs (CBMSCs) are similarly low immunogenic but much primitive compared to ASCs and more promising in large-scale commercial applications due to the extensive establishment of cord blood banks. However, whether CBMSCs and ASCs have differential therapeutic efficacy on CNI-ED and the underlying mechanisms are still not clear.Materials and methods: A bilateral cavernous nerve injury (BCNI) rat model was established by crushing the bilateral cavernous nerves. After crushing, ASCs and CBMSCs were intracavernously injected immediately. Erectile function, Masson staining, and immunofluorescence analyses of penile tissues were assessed at 4 and 12 weeks. PKH-26-labeled ASCs or CBMSCs were intracavernously injected to determine the presence and differentiation of ASCs or CBMSCs in the penis 3 days after injection. In vitro experiments including intracellular ROS detection, mitochondrial membrane potential assay, EdU cell proliferation staining, cell apoptosis assay, and protein chip assay were conducted to explore the underlying mechanism of CBMSC treatment compared with ASC treatment.Results: CBMSC injection significantly restored erectile function, rescued the loss of cavernous corporal smooth muscles, and increased the ratio of smooth muscle to collagen. PKH-26-labeled CBMSCs or ASCs did not colocalize with endothelial cells or smooth muscle cells in the corpus cavernosum. Moreover, the conditioned medium (CM) of CBMSCs could significantly inhibit the oxidative stress and elevate the mitochondria membrane potential and proliferation of Schwann cells. Better therapeutic effects were observed in the CBMSC group than the ASC group both in vivo and in vitro. In addition, the content of neurotrophic factors and matrix metalloproteinases in CBMSC-CM, especially NT4, VEGF, MMP1, and MMP3 was significantly higher than that of ASC-CM.Conclusion: Intracavernous injection of CBMSCs exhibited a better erectile function restoration than that of ASCs in CNI-ED rats owing to richer secretory factors, which can promote nerve regeneration and reduce extracellular matrix deposition. CBMSC transplantation would be a promising therapeutic strategy for CNI-ED regeneration in the future.

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Circulating matrix metalloproteinases and their endogenous inhibitors in patients with erectile dysfunction

Cited by 11 publications

References 35 publications

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

Dysregulated mitogen-activated protein kinase and matrix metalloproteinase in ethanol-induced cavernosal dysfunction

Comparison of the therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells and adipose-derived stem cells on erectile dysfunction in a rat model of bilateral cavernous nerve injury

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