Proteomic basis of modulation of post ischemic fibrosis by MSC exosomes

Following an ischemic event, there is activation of fibroblasts leading to scar formation. It is critical to limit the pro-fibrotic remodeling and activate the reparative, remodeling phase to limit cardiac diastolic dysfunction. Mesenchymal stem cell (MSC) exosomes offer significant protection against ischemia-related systolic dysfunction. Here we studied if MSC exosomes would offer protection against pro-fibrotic events in mouse hearts subjected to acute ischemia (1 hr. left coronary artery occlusion [LCA]) or chronic ischemia (7 days LCA occlusion). Following acute ischemia, there was activation of inflammatory signals, more in the peri-infarct than in the infarct area, in the saline (vehicle)-treated mice. At the same time, there was expression of cardiac remodeling signals (vimentin, collagens-1 and -3, and fibronectin), more in the infarct area. Treatment with MSC exosomes before LCA ligation suppressed inflammatory signals during acute as well as chronic ischemia. Further, exosome treatment promoted pro-reparative cardiac ECM remodeling, in both infarct and peri-infarct areas by suppressing fibronectin secretion and by modulating collagen secretion to reduce fibrotic scar formation through altered cellular signaling pathways. Proteomics study revealed intense expression of IL-1b and activation of pro-fibrotic signals in the saline-treated hearts and their suppression in MSC exosome-treated hearts. To our knowledge, this is the first report on the infarct and peri-infarct area proteomics of ischemic mice hearts to explain MSC exosome-mediated suppression of scar formation in the ischemic mouse hearts.

Roles of Angioplasty With Drug-Coated Balloon for Chronic Ischemia in Wound Healing

Purpose: Clinical trials have demonstrated sustained benefits of drug-coated balloon (DCB) angioplasty compared with noncoated balloon angioplasty in symptomatic peripheral artery disease (PAD) presenting with femoropopliteal (FP) artery disease. However, there is still controversy whether particulate embolization caused by crystalline paclitaxel, the so-called “downstream effect,” is adversely associated with clinical outcomes after use of FP DCB among chronic limb-threatening ischemia (CLTI) patients. The current RADISH (Roles of Angioplasty with Drug-coated balloon for chronic ISchemia in wound Healing) study investigated wound healing following DCB therapy vs non-DCB therapy for real-world CLTI patients presenting with FP lesions. Materials and Methods: This multicenter, retrospective study analyzed 927 patients with CLTI (mean age, 76±10 years; male, 57.8%; diabetes mellitus, 64.5%; dialysis, 50.7%) presenting with FP lesions and treated endovascularly via DCB (138 patients) vs non-DCB therapy (789 patients) between April 2014 and March 2019. The primary outcome measure was 1-year wound healing, while the secondary outcome measure was 1-year primary patency. Clinically-driven target lesion revascularization (CD-TLR), limb salvage and overall survival were also analyzed by using propensity score matching analysis. Results: The propensity score matching extracted 111 pairs (as many patients in the DCB group and 629 patients in the non-DCB group). The 1-year cumulative incidence of wound healing (95% CI) was 74.4% (62.6% to 82.5%) in the DCB group and 71.9% (60.4% to 80.1%) in the non-DCB group, with no significant intergroup difference (p=0.93). The DCB group had a higher rate of primary patency (p=0.002) and freedom from CD-TLR (p=0.010) than the non-DCB group, whereas there was no significant intergroup difference in limb salvage (p=0.21) or overall survival (p=0.93). Conclusion: The current analysis of data from the RADISH study demonstrated that DCB therapy did not lead to delayed wound healing and reduced restenosis rate in CLTI patients presenting FP lesions. From this results, DCB therapy would be a reasonable treatment option for CLTI patients.

Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy

Background: Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescence and their temporal pattern remain unknown. Methods and Results: Chronic renal ischemia was induced in transgenic INK-ATTAC mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage assessed. Selective clearance of highly p16Ink4a-expressing cells using intraperitoneal AP20187 starting 1, 2, or 4 weeks after RAS attenuated cellular senescence and improved stenotic-kidney function, whereas starting immediately after RAS induction was unsuccessful. Broader clearance of senescent cells using the oral senolytic combination Dasatinib and Quercetin in C57BL/6 RAS mice was more effective in clearing p21 (Cdkn1a)-positive cells and alleviating renal dysfunction and damage. Unbiased single-cell RNA-sequencing in freshly-dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. Like mice, injured human stenotic kidneys exhibited cellular senescence, suggesting that this process is conserved. Conclusions: Maladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.

Experience of endovascular treatment of patients with chronic ischemia threatening the loss of a limb

The aim of the study was to assess the technical feasibility of endovascular revascularization of the arteries of the lower extremities in the development of critical ischemia of the lower extremities (chronic ischemia with threatening limb loss), including diabetic foot syndrome. Two clinical cases of endovascular revascularization of lower limb arteries with the development of chronic ischemia with threatening limb loss and diabetic foot syndrome were analyzed. Median age was 61 (60–62) years; there was 1 male (50 %). Upon hospitalization, the risk of limb loss according to the WIfI classification was assessed in one case as high, in the other as medium. The efficiency of revascularization was 100 %. In 1 case (50 %), a second intervention was required. High amputation after surgery during the next year of follow-up was 100 % not necessary. The duration of the operation was 120–150 minutes. The survival rate during the year of follow-up after surgery was 100 %. Clinical observation demonstrates that even with the correct selection of patients, stratification of risk factors for both possible loss of a limb and the risk of surgery, as well as the correctness of the chosen tactics for revascularization of the CPR, only with an increase in the number of procedures performed, routing training and the creation of specialized centers is it possible to achieve satisfactory results in treatment of this problem, which, as the global trend shows, will worsen as the incidence of diabetes increases and the population ages

Ischemic Mitral Regurgitation: A Multifaceted Syndrome with Evolving Therapies

Dysfunction of the left ventricle (LV) with impaired contractility following chronic ischemia or acute myocardial infarction (AMI) is the main cause of ischemic mitral regurgitation (IMR), leading to moderate and moderate-to-severe mitral regurgitation (MR). The site of AMI exerts a specific influence determining different patterns of adverse LV remodeling. In general, inferior-posterior AMI is more frequently associated with regional structural changes than the anterolateral one, which is associated with global adverse LV remodeling, ultimately leading to different phenotypes of IMR. In this narrative review, starting from the aforementioned categorization, we proceed to describe current knowledge regarding surgical approaches in the management of IMR.

Tetrahydrobiopterin prevents chronic ischemia-related lower urinary tract dysfunction through the maintenance of nitric oxide bioavailability

This study aimed to investigate the influence of chronic ischemia on nitric oxide biosynthesis in the bladder and the effect of administering tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), on chronic ischemia-related lower urinary tract dysfunction (LUTD). This study divided male Sprague–Dawley rats into Control, chronic bladder ischemia (CBI) and CBI with oral BH4 supplementation (CBI/BH4) groups. In the CBI group, bladder capacity and bladder muscle strip contractility were significantly lower, and arterial wall was significantly thicker than in Controls. Significant improvements were seen in bladder capacity, muscle strip contractility and arterial wall thickening in the CBI/BH4 group as compared with the CBI group. Western blot analysis of bladder showed expressions of eNOS (p = 0.043), HIF-1α (p < 0.01) and dihydrofolate reductase (DHFR) (p < 0.01), which could regenerate BH4, were significantly higher in the CBI group than in Controls. In the CBI/BH4 group, HIF-1α (p = 0.012) and DHFR expressions (p = 0.018) were significantly decreased compared with the CBI group. Our results suggest that chronic ischemia increases eNOS and DHFR in the bladder to prevent atherosclerosis progression. However, DHFR could not synthesize sufficient BH4 relative to the increased eNOS, resulting in LUTD. BH4 supplementation protects lower urinary tract function by promoting eNOS activity.

Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.

Ischemic cardiopathy in medicine practice

Ischemic cardiopathy is a clinical morphological variant of IHD. It occurs due to chronic ischemia of the myocardial sites. It is characterized by the angiosclerosis of the vessels of the microvasculature, cardiosclerosis, dilatation and eccentric hypertrophy of the left ventricle, progressive heart failure.