Ali Hama Amin

Modified multipotent stromal cells with epidermal growth factor restore vasculogenesis and blood flow in ischemic hind-limb of type II diabetic mice

Diabetes is increasing in the world and causes severe cardiovascular complications. Diabetes-induced limb ischemia leads to foot amputation and therapeutic remedies are urgently needed. Here we report that local injection of mesenchymal stem cells (MSCs) prestimulated with epidermal growth factor (EGF) restored blood flow and vasculogenesis in the ischemic hind-limb of type II diabetic (db−/db−) mice. Bone marrow cells from db−/db− mice are altered as evidenced by increased oxidative stress and reduced Akt and adhesion molecules when compared with control (db−/db+). Femoral artery ligation-induced ischemia was performed in the hind-limb of db−/db− and db−/db+ mice for 28 days. Enhanced green fluorescent protein (EGFP)-MSCs stimulated±exogenous EGF for 24 h were injected locally into the ischemic muscle. Blood flow measured with MoorLDI-Laser and microangiography assessed with X-ray showed 100% recovery in db−/db+ compared to 50% recovery in db−/db− mice. Interestingly, db−/db− mice had 60 and 96% blood flow recovery and 61 and 98% of vasculogenesis when treated with MSCs alone or MSCs modified with EGF, respectively. Western blot analysis of hind-limb muscles revealed an increase in Akt and vascular endothelial growth factor receptor phosphorylation and hypoxia-inducible factor) expression in db−/db− mice injected with MSCs or MSCs+EGF compared to db−/db− mice. Fluorescent microscopic images show that EGFP-MSCs differentiate into new microvessels. Adhesion and migration of MSCs on cultured endothelial cells were ICAM1-, VCAM1- and Akt-dependent mechanism and elevated when MSCs were prestimulated with EGF compared with nonstimulated MSCs. Our novel study data provide evidence that in type II diabetes, stimulated MSCs with EGF enhance the recovery of blood flow and angiogenesis.

Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice

Endoplasmic reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischaemia‐induced neovascularization in type II diabetes is unknown. We studied ischaemia‐induced neovascularization in the hind‐limb of 4‐week‐old db − /db− mice and their controls treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) and interleukin‐1 receptor antagonist (anakinra, 0.5 µg/mouse per day) for 4 weeks. Blood pressure was similar in all groups of mice. Blood glucose, insulin levels, and body weight were reduced in db − /db− mice treated with TUDCA. Increased cholesterol and reduced adiponectin in db − /db− mice were restored by TUDCA and anakinra treatment. ER stress and inflammation in the ischaemic hind‐limb in db − /db− mice were attenuated by TUDCA and anakinra treatment. Ischaemia‐induced neovascularization and blood flow recovery were significantly reduced in db − /db− mice compared to control. Interestingly, neovascularization and blood flow recovery were restored in db − /db− mice treated with TUDCA or anakinra compared to non‐treated db − /db− mice. TUDCA and anakinra enhanced eNOS‐cGMP, VEGFR2, and reduced ERK1/2 MAP‐kinase signalling, while endothelial progenitor cell number was similar in all groups of mice. Our findings demonstrate that the inhibition of ER stress and inflammation prevents impaired ischaemia‐induced neovascularization in type II diabetic mice. Thus, ER stress and inflammation could be potential targets for a novel therapeutic approach to prevent impaired ischaemia‐induced vascular pathology in type II diabetes. Copyright

Mechanisms of myogenic tone of coronary arteriole: Role of down stream signaling of the EGFR tyrosine kinase.

BACKGROUND AND PURPOSE we previously showed that epidermal growth factor receptor tyrosine kinase (EGFRtk) is essential in the development of myogenic tone. GRB2-SOS, protein kinase B (Akt), Janus kinase (JAK), and Signal Transducer and Activator of Transcription 3 (STAT3) are activated by stretch. Thus, we hypothesized that GRB2-SOS, Akt, JAK and STAT3 are downstream signaling of the EGFR and play role in myogenic tone. EXPERIMENTAL APPROACH myogenic tone was determined in freshly isolated coronary arterioles from C57/BL6 mice with and without inhibitors. Pressurized coronary arterioles under 25 and 75mm Hg were subjected to Western blot analysis to determine signaling phosphorylation. Smooth muscle cells (SMC) stimulated with EGF were used to determine the interaction between signaling. KEY RESULTS coronary arteriole myogenic tone was significantly reduced under EGFRtk, GRB2-SOS, JAK, and STAT3 inhibition (53.6 ± 2 vs. 83.4 ± 1.3; 82.8 ± 1; 83.6 ± 1; 86.1 ± 1% of passive diameter at 75mm Hg, p<0.05, respectively). However, Akt inhibition had no effect on coronary arteriole myogenic tone. Western blot analysis showed increased EGFRtk, STAT3, JAK, and Akt phosphorylation at 75mm Hg, which was significantly inhibited under EGFRtk inhibition. Interestingly, immunoprecipitation/Western blot analysis showed two intracellular complexes (ERK1/2-JAK-STAT3) involved in myogenic tone and (Akt-JAK-STAT3) not involved in myogenic tone. CONCLUSION AND IMPLICATIONS these findings demonstrate that ERK1/2-JAK-STAT3 complex and GRB2-SOS, down stream signaling of the EGFRtk, are critical in the development of myogenic tone, thereby highlighting these signaling events as potential therapeutic targets in cardiovascular disease states associated with altered myogenic tone.

PREDICTION OF CARDIAC MECHANICAL RELAXATION ABNORMALITIES FROM SURFACE ECG WAVELETS: REPLICATION IN TWO COHORTS

The impairment of myocardial relaxation is a common finding in left ventricular diastolic dysfunction(LVDD)and is a strong predictor of cardiovascular and all-cause mortality. The electrical and mechanical domains of cardiac function are closely coupled. Consequently, subtle changes in the myocardial electrical milieu may lead to myocardial relaxation abnormalities. These small changes in the surface ECG frequency spectrum can be magnified using signal-processing techniques.

PATIENT-SPECIFIC 4D DIGITAL CLONING SIMULATION PREDICTS TRANSCATHETER AORTIC VALVE REPLACEMENT

Prediction of aortic root geometry and occurrence of paravalvular leak (PVL) following transcatheter aortic valve replacement (TAVR) is imprecise using current imaging modalities. A novel high resolution 4D computer modeling methodology was examined in order to investigate the mechanical interaction

EMERGENT ECHOCARDIOGRAPHY-GUIDED TRANSCATHETER AORTIC VALVE REPLACEMENT IN A SEVERE AORTIC STENOSIS PATIENT PRESENTING WITH CARDIAC ARREST

Patients with severe aortic stenosis presenting with cardiac arrest and cardiogenic shock may not be offered transcatheter aortic valve replacement (TAVR) due to the substantial morbidity and mortality of emergent TAVR. 69-year-old male with aortic stenosis, hypertension, and hyperlipidemia

RACIAL DISPARITY IN AORTIC VALVE REPLACEMENT OUTCOMES: INSIGHT FROM NATIONAL INPATIENT SAMPLE

Introductions: The Society of Thoracic Surgeons’ risk score identifies the AA and Hispanic races as an independent risk factor for perioperative morbidity but not mortality in patients undergoing isolated AVR. We aim to investigate the effect of race on mortality and morbidity of AVR in a large