Nabeel Abdulrahman

Na + /H + Exchanger Isoform 1-Induced Osteopontin Expression Facilitates Cardiomyocyte Hypertrophy

Enhanced expression and activity of the Na+/H+ exchanger isoform 1 (NHE1) has been implicated in cardiomyocyte hypertrophy in various experimental models. The upregulation of NHE1 was correlated with an increase in osteopontin (OPN) expression in models of cardiac hypertrophy (CH), and the mechanism for this remains to be delineated. To determine whether the expression of active NHE1-induces OPN and contributes to the hypertrophic response in vitro, cardiomyocytes were infected with the active form of the NHE1 adenovirus or transfected with OPN silencing RNA (siRNA-OPN) and characterized for cardiomyocyte hypertrophy. Expression of NHE1 in cardiomyocytes resulted in a significant increase in cardiomyocyte hypertrophy markers: cell surface area, protein content, ANP mRNA and expression of phosphorylated-GATA4. NHE1 activity was also significantly increased in cardiomyocytes expressing active NHE1. Interestingly, transfection of cardiomyocytes with siRNA-OPN significantly abolished the NHE1-induced cardiomyocyte hypertrophy. siRNA-OPN also significantly reduced the activity of NHE1 in cardiomyocytes expressing NHE1 (68.5±0.24%; P<0.05), confirming the role of OPN in the NHE1-induced hypertrophic response. The hypertrophic response facilitated by NHE1-induced OPN occurred independent of the extracellular-signal-regulated kinases and Akt, but required p90-ribosomal S6 kinase (RSK). The ability of OPN to facilitate the NHE1-induced hypertrophic response identifies OPN as a potential therapeutic target to reverse the hypertrophic effect induced by the expression of active NHE1.

Na+/H+ exchanger isoform 1-induced osteopontin expression facilitates cardiac hypertrophy through p90 ribosomal S6 kinase

Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+/H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.

Cisplatin based therapy: the role of the mitogen activated protein kinase signaling pathway

Cisplatin is a widely used chemotherapeutic agent for treatment of various cancers. However, treatment with cisplatin is associated with drug resistance and several adverse side effects such as nephrotoxicity, reduced immunity towards infections and hearing loss. A Combination of cisplatin with other drugs is an approach to overcome drug resistance and reduce toxicity. The combination therapy also results in increased sensitivity of cisplatin towards cancer cells. The mitogen activated protein kinase (MAPK) pathway in the cell, consisting of extracellular signal regulated kinase, c-Jun N-terminal kinase, p38 kinases, and downstream mediator p90 ribosomal s6 kinase (RSK); is responsible for the regulation of various cellular events including cell survival, cell proliferation, cell cycle progression, cell migration and protein translation. This review article demonstrates the role of MAPK pathway in cisplatin based therapy, illustrates different combination therapy involving cisplatin and also shows the importance of targeting MAPK family, particularly RSK, to achieve increased anticancer effect and overcome drug resistance when combined with cisplatin.

The role of CD44, hyaluronan and NHE1 in cardiac remodeling

ABSTRACT Cardiac remodeling, characterized by excessive extracellular matrix (ECM) remodeling, predisposes the heart to failure if left unresolved. Understanding the signaling mechanisms involved in excessive extracellular matrix (ECM) remodeling is necessary to identify the means to regress the development of cardiac remodeling and heart failure. Recently, hyaluronan (HA), a ubiquitously expressed glycosaminoglycan in the ECM, was shown to participate in tissue fibrosis and myofibroblast proliferation through interacting with its ubiquitously expressed cell‐surface receptor, CD44. CD44 is a multifunctional transmembrane glycoprotein that serves as a cell‐surface receptor for a number of ECM proteins. The mechanism by which the interaction between CD44‐HA contributes to ECM and cardiac remodeling remains unknown. A previous study performed on a non‐cardiac model showed that CD44‐HA enhances Na+/H+ exchanger isoform‐1 (NHE1) activity, causing ECM remodeling, HA metabolism and tumor invasion. Interestingly, NHE1 has been demonstrated to be involved in cardiac remodeling and myocardial fibrosis. In addition, it has previously been demonstrated that CD44 is upregulated in transgenic mouse hearts expressing active NHE‐1. The role of CD44, HA and NHE1 and the cellular interplay of these factors in the ECM and cardiac remodeling is the focus of this review. Graphical abstract Figure. No caption available.

The Efficacy of Etoposide on H9c2 Cardiomyoblasts Against Doxorubicin Induced Cardiotoxicity

Background: Doxorubicin (DOX), a widely used anticancer drug, has been associated with cardiotoxicity. Recently, DOX-induced cardiotoxicity has been attributed to topoisomerase II (TOPII)-β expression and activity. In our study, we investigated the effect of inhibiting TOPII in attenuating the DOX induced cardiotoxicity. Method: H9c2 cardiomyoblasts were treated with 1 or 2 μM DOX (+/-) 1 μM ETO. Cardiotoxicity was assessed by examining cell viability using the MTT assay, hypertrophy of crystal violet stained cardiomyoblasts and ROSproduction. Results: DOX induced a dose dependent increase in cardiotoxicity as indicated by the significant reduction in cell viability (71.77 ± 9.25% 2 μM DOX vs. 100% control, P<0.05), ROS production and hypertrophy. Stimulation of H9c2 cardiomyoblasts with both 2 μM DOX and 1μM ETO did not show a significant difference in cell viability, ROS production or hypertrophy. Conclusion: DOX induced cardiotoxicity in H9c2 cardiomyoblasts was not exacerbated in the presence of 1 μM ETO. This provides further support to using the combination of DOX and ETO, which is currently being done to treat advanced AIDS related sarcomas in the clinical setting.