Biomedical subjects

Nauman Ahmad

Publications and source records attributed to Nauman Ahmad.

9 recordsLinked to original sources

PubMed2007

Chronic preconditioning: a novel approach for cardiac protection.

Ischemic preconditioning is the most powerful protective mechanism known against lethal ischemia. Unfortunately, the protection lasts for only a few hours. Here we tested the hypothesis that the heart can be kept in a preconditioned state for constant protection against ischemia. In this study we chose BMS-191095 (BMS), a highly selective opener of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels. BMS (1 mg/kg ip) was administered to rats every 24 h until 96 h. In other groups, BMS plus wortmannin (WTN, 15 microg/kg ip), an inhibitor of the phosphatidylinositol 3-kinase (PI3-K), or BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoK(ATP), or BMS plus N(omega)-nitro-L-arginine methyl ester (L-NAME) (30 microg/kg ip), an inhibitor of nitric oxide (NO) synthase, were administered to rats. Rats were then subjected to 30-min left anterior descending coronary artery occlusion and 120-min reperfusion. Cardiac function, infarct size, pathological changes, and apoptosis were assessed at the end of treatments. Saline-treated hearts displayed marked contractile dysfunction and underwent pathological changes. BMS-treated rats showed significant improvement in cardiac function, and infarct size was significantly reduced in BMS-treated hearts. However, protection by BMS was abolished by 5-HD, WTN, or L-NAME. These data demonstrate that hearts can be chronically preconditioned and retain their ability to remain resistant against lethal ischemia and that this protection is mediated by activation of mitoK(ATP) via NO and PI3-K/Akt signaling pathways.

Animals↗

PubMed2006

Evidence for ischemia induced host-derived bone marrow cell mobilization into cardiac allografts.

Mobilized bone marrow stem cells (BMSC) exhibit high degree of plasticity and participate in the repair process in the event of myocardial damage. In this study, we verified the proportional contribution of recipient BMSC in the repair process and identified their specific surface markers. Wild-type (WT) donor female heart was transplanted into abdominal cavity of male rat (Group I). In some of recipient animals, infarction was created by LAD occlusion (Group II). Two weeks later, transplanted female hearts were harvested for histological analysis of the mobilized cells. C-kit, CD31, Ki67 and Y-chromosome were used as markers to identify mobilized cells in the female hearts. Y-chromosome positive cells were found in the donor female cardiac allografts. Acute myocardial infarction (AMI) of recipient heart induced migration of progenitor cells into the lesions of chronic rejection in the allograft. Donor ventricular mass reduction was more pronounced in Group I. Endothelial progenitor cells induced by AMI from male recipient extensively migrated into the cardiac allograft. SDF-1 mRNA levels significantly increased (peak level at 24 h after AMI) in recipient heart. CXCR4 was strongly expressed in the transplanted hearts around the perivascular area. Spontaneous mobilization of hematopoietic progenitor cells (HPCs) occurred in cardiac allografts after creating recipient heart AMI and was detectable until 2 weeks. These data suggests that CXCR4 overexpression enhances vascularization in the damaged myocardium and SDF-1/CXCR4 axis seems particularly important in progenitor cell chemotaxis, homing, engraftment and retention in damaged myocardium. In addition, BMSC attracted to the site of ischemic injury participate in cardiac repair.

Animals↗

PubMed2006

Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling.

In this study, we hypothesized that bone marrow stem cells (BMSCs) protect ischemic myocardium through paracrine effects that can be further augmented with preconditioning. In in vitro experiments, cell survival factors such as Akt and eNOS were significantly increased in BMSCs following anoxia. In the second series of experiments following coronary ligation in mice, left ventricles were randomly injected with the following: DMEM (G-1), BMSCs (G-2), and preconditioned BMSCs (G-3). Four days after myocardial infarction, BMSCs were observed within injured myocardium in G-2 and G-3. Apoptotic cardiomyocytes within periinfarct area were significantly reduced in G-3. Four weeks after myocardial infarction, smaller left ventricular (LV) dimension and increased LV ejection fraction were observed in G-3. Infarct area was significantly reduced in G-3. However, GFP+ cardiomyocytes were observed in low numbers within periinfarct area in G-2 and G-3. In conclusion, BMSCs secreted cell survival factors under ischemia, and they prevented apoptosis in cardiomyocytes adjacent to the infarcted area. Preconditioning of BMSCs enhanced their survival and ability to attenuate LV remodeling, which was attributable, in part, to paracrine effects.

Animals↗

PubMed2006

Combining pharmacological mobilization with intramyocardial delivery of bone marrow cells over-expressing VEGF is more effective for cardiac repair.

We postulated that combining cell based hVEGF165 gene delivery with cytokine-induced mobilization of bone marrow cells (BMC) may give better prognosis in an infarcted heart. Forty-eight myoabalated female C57BL/6J mice (20-25 g) received 1 x 10(6) BMC from transgenic GFP+ male mice. One month later, acute myocardial infarction (MI) model was developed by coronary artery ligation. Animals were grouped (N = 12) to receive intramyocardial injections of 10 microl DMEM without cells (group 1; group 2) or with 1x10(5) mesenchymal stem cells (MSC) over-expressing hVEGF165 (group 3; group 4). The animals received either cytokine therapy (group 2 and 4) or saline solution (group 1 and 3) for 7 days after MI. Hemodynamic data were obtained 4 weeks after MI using Millar's P-V system and cardiac tissue was harvested for immunohistological studies. We observed regeneration and extensive survival of BMC in and around the infarcted myocardium in groups 3 and 4. Blood vessel density was markedly enhanced in group 4 as compared with groups 1 and 2 in peri-infarct area. Fibrotic area was significantly reduced with improved LV-contractile function in group 2 and 4. LV-systolic and diastolic functions were well-preserved in group 4 as indicated by +dP/dt, -dP/dt and Tau (glantz). We therefore conclude that transplantation of MSC overexpressing VEGF combined with cytokine induced BMC mobilization is superior to either of the monotherapy approach for angiomyogenesis and LV-function recovery.

Animals↗

PubMed2006

Cardiac protection by mitoKATP channels is dependent on Akt translocation from cytosol to mitochondria during late preconditioning.

This investigation elucidates the Akt/mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel signaling pathway in late pharmacological preconditioning, using the mitoK(ATP) channel openers BMS-191095 (BMS) and diazoxide (DE). BMS (1 mg/kg ip) and DE (7 mg/kg ip) alone or BMS plus wortmannin (WTN, 15 microg/kg ip), an inhibitor of phosphatidylinositol 3-kinase, and BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoK(ATP) channels, were administered to male mice. Twenty-four hours later, hearts were isolated and subjected to 40 min of ischemia and 120 min of reperfusion via Langendorff's apparatus. Both BMS and DE reduced left ventricular end-diastolic pressure and increased left ventricular developed pressure as well as reduced LDH release. Coadministration of BMS and WTN abolished the beneficial effects of BMS on cardiac function. Moreover, BMS and DE accelerated Akt phosphorylation in cardiac tissue as determined by Western blot analysis and also significantly reduced apoptosis compared with ischemic control. WTN significantly suppressed BMS-induced Akt phosphorylation, whereas 5-HD had no effect on Akt phosphorylation in cytosol, and the effect of BMS on apoptosis was abolished. It is concluded that the cardioprotective effect by mitoK(ATP) channels is attributed to the translocation of phosphorylated Akt from cytosol to mitochondria.

Androstadienes↗

PubMed2005

Mechanisms by which K(ATP) channel openers produce acute and delayed cardioprotection.

Mitochondria are being increasingly studied for their critical role in cell survival. Multiple diverse signaling pathways have been shown to converge on the K+-sensitive ATP channels as the effectors of cytoprotection against necrosis and apoptosis. The role of potassium channel openers in regulation and transformation of cell membrane excitability, action potential and electrolyte transfer has been extensively studied. Cardiac mitoK(ATP) channels are the key effectors in cardioprotection during ischemic preconditioning, as yet with an undefined mechanism. They have been hypothesized to couple myocardial metabolism with membrane electrical activity and provide an excellent target for drug therapy. A number of K(ATP) channel openers have been characterized for their beneficial effects on the myocardium against ischemic injury. This review updates recent progress in understanding the physiological role of K(ATP) channels in cardiac protection induced by preconditioning and highlights relevant questions and controversies in the light of published data.

Animals↗

PubMed2004

Contribution of Akt and endothelial nitric oxide synthase to diazoxide-induced late preconditioning.

The opening of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels has a significant role in delayed ischemic preconditioning, and nitric oxide (NO) is a well-known trigger for its activation. However, the source of NO remains unknown. Phosphorylation of endothelial NO synthase (eNOS) increases NO production and reduces apoptosis through the Akt signaling pathway. To elucidate the Akt signaling pathway involved in the opening and antiapoptotic effect of mitoKATP channel during delayed pharmacological preconditioning, the mitoKATP channel opener diazoxide (DE, 7 microg/kg i.p.) alone or DE plus Nomega-nitro-L-arginine methyl ester (L-NAME, 30 microg/kg i.v.), an inhibitor of NOS, or wortmannin (WTN, 15 microg/kg i.v.), an inhibitor of phosphatidylinositol 3'-kinase (PI3 kinase), was administered to wild-type (WT) or eNOS(-/-) mice during DE treatment. Twenty-four hours later, hearts were isolated and subjected to 40 min ischemia and 30 min reperfusion (I/R). The effect of DE and other interventions on hemodynamic, terminal dUTP nick-end labeling staining and biochemical changes during I/R was assessed in mouse hearts. Treatment with DE resulted in a 2.2-fold increase in phosphorylation of Akt and a significant increase in eNOS and inducible NOS (iNOS) proteins. Akt is upstream of NOS and the mitoKATP channel as simultaneous pretreatment of WTN with DE abolished phosphorylation of Akt, which was not affected by L-NAME and 5-hydroxydecanoate. In hearts treated with DE, cardiac function was significantly improved after I/R, and apoptosis was also significantly decreased. WTN abolished the antiapoptotic effect of DE. Similarly, S-methylisothiourea, a specific iNOS inhibitor, when given to eNOS(-/-) mice that were pretreated with DE completely abolished the beneficial effects of DE on reduction of apoptotic death. DE was partially effective in eNOS(-/-) mice against the ischemic injury. It is concluded that DE activates Akt through the PI3 kinase signaling pathway and iNOS and eNOS is downstream of Akt.

Animals↗

PubMed2004

Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis.

This study determines the effect of hepatocyte growth factor (HGF) on post-infarction left ventricular (LV) remodeling and cardiac function. In mice, on day 1 after myocardial infarction (MI), HGF (0.45 mg/kg per day) was injected into the tail vein for 7 days (n = 12). In the control mice (n = 12), 0.9% sodium chloride was injected instead of HGF. Hemodynamic data were obtained in vehicle treated control and HGF-treated hearts 4 weeks after the onset of MI. In the HGF-treated group, cardiac function was well preserved as indicated by LV pressure-volume relationship. These mice exhibited better LV systolic and diastolic function. The infarcted LV wall in HGF-treated heart was thicker as compared to vehicle treated group. Fibrosis and infarct size of the ventricular wall was significantly reduced in the HGF-treated hearts. 5-Bromo-2'-deoxy-uridine (BrdU) and Ki67 positive cardiomyocytes were observed in the border area of the HGF-treated infarcted hearts. c-Met and c-kit positive cardiomyocytes were observed in the border area and epicardium. Angiogenesis was significantly enhanced in HGF-treated hearts as determined by vessel density per unit area. A significant reduction in apoptosis in the HGF-treated hearts was observed compared with control hearts, and was strongly associated with increased Akt activation. Treatment with HGF improved heart function through angiogenesis, ventricular wall thickening, and hypertrophy of cardiomyocytes. The antiapoptotic effect of HGF was mediated by activation of PI3-kinase/Akt pathway.

Animals↗

PubMed2003

Significant variables associated with epilepsy.

OBJECTIVE: To study the characteristics of the epileptics and the risk factors contributing to the development of epilepsy. DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Epilepsy Clinic at Ahbab Hospital, Lahore, from June 2002 to August 2002. SUBJECTS AND METHODS: Data was collected from 158 subjects, 89 males and 69 females, suffering from epilepsy. The information about socio-demographic characteristics and family history of illness, perinatal morbidity, birth place and mother s age at the time of delivery was obtained using a pre-tested questionnaire. Data was analyzed on SPSS version 10. RESULTS: Majority of the subjects were single (77.84%), 1st born among their siblings (25.95%), belonged to low social class (50.63%), and unemployed (25.31%). The major risk factors were family history of illness (23.52%) and positive medical problem around birth (12.66%). The presence of family history of illness, positive medical problem around birth and advanced maternal age at birth were associated with early onset of epilepsy. Vulnerability for the epilepsy also increases among hospital deliveries. CONCLUSION: Although the present study has identified various risk factors, yet the results need to be further confirmed through case-control studies.

Adult↗