Ischemia-induced Fibrosis Research Articles

MicroRNAs-The Heart of Post-Myocardial Infarction Remodeling.

Myocardial infarction (MI) is one of the most frequent cardiac emergencies, with significant potential for mortality. One of the major challenges of the post-MI healing response is that replacement fibrosis could lead to left ventricular remodeling (LVR) and heart failure (HF). This process involves canonical and non-canonical transforming growth factor-beta (TGF-β) signaling pathways translating into an intricate activation of cardiac fibroblasts and disproportionate collagen synthesis. Accumulating evidence has indicated that microRNAs (miRNAs) significantly contribute to the modulation of these signaling pathways. This review summarizes the recent updates regarding the molecular mechanisms underlying the role of the over 30 miRNAs involved in post-MI LVR. In addition, we compare the contradictory roles of several multifunctional miRNAs and highlight their potential use in pressure overload and ischemia-induced fibrosis. Finally, we discuss their attractive role as prognostic biomarkers for HF, highlighting the most relevant human trials involving these miRNAs.

Melatonin suppresses ischemia-induced fibrosis by regulating miR-149

Ischemic injury is a major risk factor for fibrosis. However, the precise mechanisms by which fibrosis is regulated and induced under ischemic oxidative stress conditions are unknown. To address this, we investigated the effect of melatonin on ischemia-induced fibrosis. In a hindlimb ischemia mouse model, ischemia induced fibrosis by increasing inflammation and the expression of extracellular matrix (ECM) proteins. Melatonin prevented ischemia-induced fibrosis in the injured tissues. In particular, melatonin suppressed the fibrosis-mediated inflammatory reaction in myoblasts through the microRNA-149 (miR-149)/indoleamine 2,3-dioxygenase-1 (IDO-1) signaling pathway. The melatonin-induced increase in miR-149 inhibited the expression of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and ECM components, such as collagen I and fibronectin. In addition, melatonin increased antioxidative activity and mitochondrial function in myoblasts via the miR-149/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) signaling axis, and the anti-fibrotic effects of melatonin were blocked by inhibition of miR-149. These findings indicate that melatonin is a key target molecule in fibrosis related to ischemic diseases and that miR-149 might be a novel target for the treatment of ischemia-induced fibrosis.

Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury

BackgroundAcute kidney injury (AKI) is an underestimated, yet important, risk factor for the development of chronic kidney disease (CKD). Persistence of inflammation after a renal ischemic injury has been observed, both in experimental models and patients, and is thought to be an important mechanisms underlying progression of acute-to-chronic renal injury. Temporary suppression of inflammation immediately after AKI might therefore be a good first-line therapeutic strategy towards a better long term outcome.MethodsMale C57Bl/6 J mice (Charles River, 10–12 weeks of age) underwent warm (36 °C body temperature) unilateral ischemia-reperfusion of the kidney for 21 min, after which treatment with intraperitoneal injection of the corticosteroid dexamethasone (10 mg/kg) was initiated for 3 weeks. Both at that time point and after an additional 3 week post-treatment follow up period, fibrosis was quantified by collagen I gene expression and immunostaining, as well as gene expression analysis of fibrosis-related genes Tgfβ, Ccn2 (Ctgf), Pai-1 and Ccn3. Furthermore, inflammation was evaluated by Tnfα gene expression and protein expression of the F4/80 macrophage marker and the α-SMA fibroblast marker. Lastly, renal histopathology was quantified by a morphometric analysis of the tubulointerstitial area.ResultsTreatment with dexamethasone attenuated development of fibrosis, as evidenced by reduced collagen I gene expression and immunostaining, in combination with reduced gene expression of the pro-fibrotic Ccn2 and increased expression of the anti-fibrotic Ccn3. The effects of dexamethasone on renal fibrosis persisted during the 3 week follow up period, as evidenced by stagnation of collagen I deposition in the ischemic kidney, in contrast to vehicle-treatment, where progression of fibrosis was observed. However, expression levels of the pro-fibrotic genes re-approached those of vehicle-treated injured kidneys suggesting that the effects of dexamethasone on fibrosis beyond the treatment period are temporary.ConclusionA short term anti-inflammatory therapy with dexamethasone only transiently attenuates ischemia induced fibrosis. Prolonged or persistent anti-inflammatory treatment seems warranted to achieve long term benefit.

Endothelial Colony Forming Cells (ECFCs) in murine AKI \u2013 implications for future cell-based therapies

BackgroundIn recent years, early Endothelial Progenitor Cells (eEPCs) have been proven as effective tool in murine ischemic AKI and in diabetic nephropathy. The mechanisms of eEPC-mediated vasoprotection have been elucidated in detail. Besides producing a diverse range of humoral factors, the cells also act by secreting vasomodulatory microvesicles. Only few data in contrast have been published about the role of so-called Endothelial Colony Forming Cells (ECFCs - late EPCs) in ischemic AKI. We thus aimed to investigate ECFC effects on postischemic kidney function over several weeks. Our special interest focused on endothelial-to-mesenchymal transition (EndoMT), peritubular capillary density (PTCD), endothelial alpha-Tubulin (aT - cytoskeletal integrity), and endothelial p62 (marker of autophagocytic flux).MethodsEight to twelve weeks old male C57Bl/6 N mice were subjected to bilateral renal pedicle clamping for 35 or 45 min, respectively. Donor-derived syngeneic ECFCs (0.5 × 106) were i.v. injected at the end of ischemia. Animals were analyzed 1, 4 and 6 weeks later.ResultsCell therapy improved kidney function exclusively at week 1 (35 and 45 min). Ischemia-induced fibrosis was diminished in all experimental groups by ECFCs, while PTCD loss remained unaffected. Significant EndoMT was detected in only two of 6 groups (35 min, week 4 and 45 min, week 6), ECFCs reduced EndoMT only in the latter. Endothelial aT declined under almost all experimental conditions and these effects were further aggravated by ECFCs. p62 was elevated in endothelial cells, more so after 45 than after 35 min of ischemia. Cell therapy did not modulate p62 abundances at any time point.ConclusionA single dose of ECFCs administered shortly post-ischemia is capable to reduce interstitial fibrosis in the mid- to long-term whereas excretory dysfunction is improved only in a transient manner. There are certain differences in renal outcome parameters between eEPCs and ECFC. The latter do not prevent animals from peritubular capillary loss and they also do not further elevate endothelial p62. We conclude that differences between eEPCs and ECFCs result from certain mechanisms by which the cells act around and within vessels. Overall, ECFC treatment was not as efficient as eEPC therapy in preventing mice from ischemia-induced mid- to long-term damage.

Pravastatin Prevents Myocardium from Ischemia-Induced Fibrosis by Protecting Vascular Endothelial Cells Exposed to Oxidative Stress

Statins potently prevents cardiac myocytes from acute ischemia besides chronic inhibition of cholesterol synthesis. We investigated how pravastatin preserves the cardiac function after myocardial infarction (MI). Echocardiographically comparing rats with myocardial ischemia (MI group) with those treated with pravastatin (MI/statin group), we found that cardiac contractility was statistically preserved in the MI/statin whereas it was deteriorated in MI group. Histochemical analysis suggested that ischemia-induced cardiac fibrosis was prevented by pravastatin. Because there was no significant myocyte apoptosis reflecting myocytes loss between two groups, ischemia-induced interstitial fibrosis might affect the contractility. We hypothesized that statin may directly affect vascular endothelial cells regulating blood supply to the myocardium rather than affecting myocytes. Pravastatin perturbed H2O2-induced endothelial NOS reduction and inhibited H2O2-increased caspase-3 activation in cultured vascular endothelial cells. These data suggested that pravastatin prevent cardiac dysfunction by acting on vascular endothelial cells. Furthermore, early administration of pravastatin to the patients during acute onset of myocardial infarction may be beneficial to prevent myocardial damage caused by fibrosis associated with ischemia.