scholarly journals Myocardial Impact of NHE1 Regulation by Sildenafil

2021 ◽  
Vol 8 ◽  
Author(s):  
Daiana S. Escudero ◽  
Néstor G. Pérez ◽  
Romina G. Díaz
Keyword(s):  
Experimental Data ◽  
Animal Models ◽  
Gold Standard ◽  
Cardiac Tissue ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Membrane Glycoprotein ◽  
Phosphorylation State ◽  
Nhe1 Activity ◽  
Inhibitor Drug

The cardiac Na+/H+ exchanger (NHE1) is a membrane glycoprotein fundamental for proper cell functioning due its multiple housekeeping tasks, including regulation of intracellular pH, Na+ concentration, and cell volume. In the heart, hyperactivation of NHE1 has been linked to the development of different pathologies. Several studies in animal models that reproduce the deleterious effects of ischemia/reperfusion injury or cardiac hypertrophy have conclusively demonstrated that NHE1 inhibition provides cardioprotection. Unfortunately, NHE1 inhibitors failed to reproduce these effects in the clinical arena. The reasons for those discrepancies are not apparent yet. However, a reasonable clue to consider would be that drugs that completely abolish the exchanger activity, including that its essential housekeeping function may not be the best therapeutic approach. Therefore, interventions tending to specifically reduce its hyperactive state without affecting its basal activity emerge as a novel potential gold standard. In this regard, a promising goal seems to be the modulation of the phosphorylation state of the cytosolic tail of the exchanger. Recent own experiments demonstrated that Sildenafil, a phosphodiesterase 5A inhibitor drug that has been widely used for the treatment of erectile dysfunction is able to decrease NHE1 phosphorylation, and hence reduce its hyperactivity. In connection, growing evidence demonstrates cardioprotective properties of Sildenafil against different cardiac pathologies, with the distinctive characteristic of directly affecting cardiac tissue without altering blood pressure. This mini-review was aimed to focus on the regulation of NHE1 activity by Sildenafil. For this purpose, experimental data reporting Sildenafil effects in different animal models of heart disease will be discussed.

Exercise alters the regulation of myocardial Na+/H+ exchanger-1 activity

2013 ◽  
Vol 305 (10) ◽  
pp. R1182-R1189 ◽  
Author(s):  
Bryan J. Feger ◽  
Joseph W. Starnes
Keyword(s):  
Intracellular Ph ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Buffering Capacity ◽  
Strenuous Exercise ◽  
Sprague Dawley ◽  
Ph Buffering ◽  
Nhe1 Activity ◽  
Ph Buffering Capacity

The myocardial Na+/H+ exchanger-1 (NHE1) plays a major role in regulation of intracellular pH, and its upregulation has been implicated in increased ischemia-reperfusion injury and other pathologies. Hydrogen peroxide (H2O2) increases NHE1 activity acutely via ERK1/2 signaling. Chronic strenuous exercise upregulates NHE1 in skeletal muscle, but we hypothesize this will not occur in the heart, because exercise creates a cardioprotective phenotype. NHE1 activity and its regulation by H2O2 were examined at physiological pH using isolated cardiomyocytes from female Sprague-Dawley rats exercised on a treadmill for 5 wk (E; n = 11). Compared with sedentary (S; n = 15), E displayed increases ( P < 0.05) in heart-to-body weight ratio (6.8%) and plantaris mitochondria content (89%). NHE1 activity (acid efflux rate following an acid load) was 209% greater in E (0.65 ± 0.12 vs. 2.01 ± 0.29 fmol/min). The difference was attributed primarily to greater cell volume (22.2 ± 0.6 vs. 34.3 ± 1.1 pl) and intracellular pH-buffering capacity (33.94 ± 1.59 vs. 65.82 ± 5.20 mM/pH unit) of E myocytes. H2O2 stimulation (100 μM) raised NHE1 activity significantly less in E (45%) than S (167%); however, activity remained 185% greater in E. ERK1/2 inhibition abrogated the increases. H2O2-stimulated ERK1/2 phosphorylation levels normalized to total ERK1/2 were similar between groups. Content of NHE1 and activities of H2O2 scavengers were also similar. We observed that intracellular pH-buffering capacity differences between groups became progressively less with declining pH, which may be an exercise-induced cardioprotective adaptation to lower NHE1 activity during certain pathological situations. We conclude that strenuous endurance exercise increases myocardial NHE1 activity at physiological pH, which would likely enhance cardiac performance under physiological conditions.

Overexpression of the Na+/H+ exchanger and ischemia-reperfusion injury in the myocardium

2007 ◽  
Vol 292 (5) ◽  
pp. H2237-H2247 ◽  
Author(s):  
Kenichi Imahashi ◽  
Fatima Mraiche ◽  
Charles Steenbergen ◽  
Elizabeth Murphy ◽  
Larry Fliegel
Keyword(s):  
Transgenic Mice ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rate Pressure Product ◽  
Protective Effects ◽  
Early Reperfusion ◽  
Heart Performance ◽  
Percent Recovery ◽  
Nhe1 Activity ◽  
Rate Limiting

In the myocardium, the Na+/H+ exchanger isoform-1 (NHE1) activity is detrimental during ischemia-reperfusion (I/R) injury, causing increased intracellular Na+ (Nai+) accumulation that results in subsequent Ca2+ overload. We tested the hypothesis that increased expression of NHE1 would accentuate myocardial I/R injury. Transgenic mice were created that increased the Na+/H+ exchanger activity specifically in the myocardium. Intact hearts from transgenic mice at 10–15 wk of age showed no change in heart performance, resting intracellular pH (pHi) or phosphocreatine/ATP levels. Transgenic and wild-type (WT) hearts were subjected to 20 min of ischemia followed by 40 min of reperfusion. Surprisingly, the percent recovery of rate-pressure product (%RPP) after I/R improved in NHE1-overexpressing hearts (64 ± 5% vs. 41 ± 5% in WT; P < 0.05). In addition, NMR spectroscopy revealed that NHE1 overexpressor hearts contained higher ATP during early reperfusion (levels P < 0.05), and there was no difference in Na+ accumulation during I/R between transgenic and WT hearts. HOE642 (cariporide), an NHE1 inhibitor, equivalently protected both WT and NHE1-overexpressing hearts. When hearts were perfused with bicarbonate-free HEPES buffer to eliminate the contribution of HCO3− transporters to pHi regulation, there was no difference in contractile recovery after reperfusion between controls and transgenics, but NHE1-overexpressing hearts showed a greater decrease in ATP during ischemia. These results indicate that the basal activity of NHE1 is not rate limiting in causing damage during I/R, therefore, increasing the level of NHE1 does not enhance injury and can have some small protective effects.

Therapeutic modulation of tissue kallikrein expression

2016 ◽  
Vol 397 (12) ◽  
pp. 1293-1297
Author(s):  
Duncan J. Campbell
Keyword(s):  
Cardiac Tissue ◽  
Enzyme Inhibitors ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Therapeutic Benefit ◽  
Tissue Kallikrein ◽  
Converting Enzyme Inhibitors ◽  
Kinin System ◽  
Kallikrein Kinin System

Abstract The kallikrein kinin system has cardioprotective actions and mediates in part the cardioprotection produced by angiotensin converting enzyme inhibitors and angiotensin type 1 receptor blockers. Additional approaches to exploit the cardioprotective effects of the kallikrein kinin system include the administration of tissue kallikrein and kinin receptor agonists. The renin inhibitor aliskiren was recently shown to increase cardiac tissue kallikrein expression and bradykinin levels, and to reduce myocardial ischemia-reperfusion injury by bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. Thus, aliskiren represents a prototype drug for the modulation of tissue kallikrein expression for therapeutic benefit.

Radicicol activates heat shock protein expression and cardioprotection in neonatal rat cardiomyocytes

2004 ◽  
Vol 287 (3) ◽  
pp. H1081-H1088 ◽  
Author(s):  
Tina M. Griffin ◽  
Tina V. Valdez ◽  
Ruben Mestril
Keyword(s):  
Heat Shock ◽  
Transcriptional Activation ◽  
Cardiac Tissue ◽  
Defense Mechanism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Heat Shock Factor 1 ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes

Heat shock proteins (HSPs) constitute an endogenous cellular defense mechanism against environmental stresses. In the past few years, studies have shown that overexpression of HSPs can protect cardiac myocytes against ischemia-reperfusion injury. In an attempt to increase the HSPs in cardiac tissue, we used the compound radicicol that activates HSP expression by binding to the HSP 90 kDa (HSP90). HSP90 is the main component of the cytosolic molecular chaperone complex, which has been implicated in the regulation of the heat shock factor 1 (HSF1). HSF1 is responsible for the transcriptional activation of the heat shock genes. In the present study, we show that radicicol induces HSP expression in neonatal rat cardiomyocytes, and this increase in HSPs confers cardioprotection to these cardiomyocytes. We also show that radicicol induction of the HSP and cardioprotection is dependent on the inhibition of HSP90 in cardiomyocytes. These results indicate that modulation of the active HSP90 protein level plays an important role in cardioprotection. Therefore, compounds, such as radicicol and its possible derivatives that inhibit the function of HSP90 in the cell may represent potentially useful cardioprotective agents.

Warm or Cold Ischemia in Animal Models of Lung Ischemia-Reperfusion Injury: Is There a Difference?

2004 ◽  
Vol 52 (3) ◽  
pp. 174-179 ◽  
Author(s):  
G. Warnecke ◽  
S. P. Sommer ◽  
B. Gohrbandt ◽  
S. Fischer ◽  
J. M. Hohlfeld ◽  
...  
Keyword(s):  
Animal Models ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cold Ischemia

scholarly journals Therapeutic Potential of Annexins in Sepsis and COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Louise Mui ◽  
Claudio M. Martin ◽  
Brent J. Tschirhart ◽  
Qingping Feng
Keyword(s):  
Animal Models ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Membrane Dynamics ◽  
Annexin A5 ◽  
Organ Function ◽  
High Prevalence ◽  
Inflammatory Processes ◽  
Significant Mortality

Sepsis is a continuing problem in modern healthcare, with a relatively high prevalence, and a significant mortality rate worldwide. Currently, no specific anti-sepsis treatment exists despite decades of research on developing potential therapies. Annexins are molecules that show efficacy in preclinical models of sepsis but have not been investigated as a potential therapy in patients with sepsis. Human annexins play important roles in cell membrane dynamics, as well as mediation of systemic effects. Most notably, annexins are highly involved in anti-inflammatory processes, adaptive immunity, modulation of coagulation and fibrinolysis, as well as protective shielding of cells from phagocytosis. These discoveries led to the development of analogous peptides which mimic their physiological function, and investigation into the potential of using the annexins and their analogous peptides as therapeutic agents in conditions where inflammation and coagulation play a large role in the pathophysiology. In numerous studies, treatment with recombinant human annexins and annexin analogue peptides have consistently found positive outcomes in animal models of sepsis, myocardial infarction, and ischemia reperfusion injury. Annexins A1 and A5 improve organ function and reduce mortality in animal sepsis models, inhibit inflammatory processes, reduce inflammatory mediator release, and protect against ischemic injury. The mechanisms of action and demonstrated efficacy of annexins in animal models support development of annexins and their analogues for the treatment of sepsis. The effects of annexin A5 on inflammation and platelet activation may be particularly beneficial in disease caused by SARS-CoV-2 infection. Safety and efficacy of recombinant human annexin A5 are currently being studied in clinical trials in sepsis and severe COVID-19 patients.

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