Characterization of Stressed Transgenic Mice Overexpressing H<sub>2</sub>-Histamine Receptors in the Heart

Gergs, Ulrich; Kirchhefer, Uwe; Bergmann, Fabian; Künstler, Bernhard; Mißlinger, N.; Au, Bastian; Mahnkopf, Mareen; Wache, Hartmut; Neumann, Joachim

doi:10.1124/jpet.120.000063

Cited by 25 publications

(39 citation statements)

References 41 publications

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“…In addition, studies have found increased ANP levels in mice with acute regional cardiac ischemia [ 57 ]. The overexpression of receptors that stimulate cAMP generation, such as H 2 receptors [ 58 ] or A 2A -adenosine receptors [ 35 ], can protect isolated left atria against acute hypoxia in the same experimental setup. Other studies have reported that cardiac ischemia in mice hearts causes increased IL-6 [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of Serotonin 5-HT4 Receptors on Responses to Cardiac Stressors in Transgenic Mouse Models

et al. 2021

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The current study aimed to deepen our knowledge on the role of cardiac 5-HT4 receptors under pathophysiological conditions. To this end, we used transgenic (TG) mice that overexpressed human 5-HT4a receptors solely in cardiac myocytes (5-HT4-TG mice) and their wild-type (WT) littermates that do not have functional cardiac 5-HT4 receptors as controls. We found that an inflammation induced by lipopolysaccharide (LPS) was detrimental to cardiac function in both 5-HT4-TG and WT mice. In a hypoxia model, isolated left atrial preparations from the 5-HT4-TG mice went into contracture faster during hypoxia and recovered slower following hypoxia than the WT mice. Similarly, using isolated perfused hearts, 5-HT4-TG mice hearts were more susceptible to ischemia compared to WT hearts. To study the influence of 5-HT4 receptors on cardiac hypertrophy, 5-HT4-TG mice were crossbred with TG mice overexpressing the catalytic subunit of PP2A in cardiac myocytes (PP2A-TG mice, a model for genetically induced hypertrophy). The cardiac contractility, determined by echocardiography, of the resulting double transgenic mice was attenuated like in the mono-transgenic PP2A-TG and, therefore, largely determined by the overexpression of PP2A. In summary, depending on the kind of stress put upon the animal or isolated tissue, 5-HT4 receptor overexpression could be either neutral (genetically induced hypertrophy, sepsis) or possibly detrimental (hypoxia, ischemia) for mechanical function. We suggest that depending on the underlying pathology, the activation or blockade of 5-HT4 receptors might offer novel drug therapy options in patients.

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Section: Discussionmentioning

confidence: 99%

Influence of Serotonin 5-HT4 Receptors on Responses to Cardiac Stressors in Transgenic Mouse Models

et al. 2021

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“…Animals were maintained and handled according to approved protocols of the animal welfare committees of the Martin Luther University of Halle-Wittenberg, Germany. The generation and initial characterization of mice with cardiac-specific overexpression have been reported from our group (Gergs et al 2019(Gergs et al , 2020Neumann et al 2021b). We used an α-myosin heavy chain promoter to overexpress the human H 2 -histamine receptor in the mouse heart and tested the offspring for transgenes using the polymerase chain reaction (Gergs et al 2019(Gergs et al , 2020Neumann et al 2021b).…”

Section: Transgenic Micementioning

confidence: 99%

Human histamine H2 receptors can initiate cardiac arrhythmias in a transgenic mouse

Gergs

Weisgut

Griethe

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

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Histamine is known to lead to arrhythmias in the human heart. A mouse model to mimic these effects has hitherto not been available but might be useful to study the mechanism(s) of H2-histamine receptor-induced arrhythmias and may support the search for new antiarrhythmic drugs. In order to establish such a model in mice, we studied here the incidence of cardiac arrhythmias under basal and under stimulated conditions in atrial and ventricular preparations from mice that overexpressed the human H2-histamine receptors in a cardiac-specific way (H2-TG) in comparison with their wild-type (WT) littermate controls. We had shown before that histamine exerted concentration and time-dependent positive inotropic and positive chronotropic effects only in cardiac preparations from H2-TG and not from WT. We noted under basal conditions (no drug addition) that right atrial preparations from H2-TG exhibited more spontaneous arrhythmias than right atrial preparations from WT. These arrhythmias in H2-TG could be blocked by the H2-histamine receptor antagonist cimetidine. In a similar fashion, histamine and dimaprit (an agonist at H2 and not H1-histamine receptors) more often induced arrhythmias in right atrial preparations from H2-TG than from WT. To understand better the signal transduction mechanism(s) involved in these arrhythmias, we studied partially depolarized left atrial preparations. In these preparations, a positive inotropic effect of histamine was still present in the additional presence of 44 mM potassium ions (used to block sodium channels) in H2-TG but not WT and this positive inotropic effect could be blocked by cimetidine and this is consistent with the involvement of calcium ion channels in the contractile and thus might mediate also the arrhythmogenic effects of histamine in H2-TG. However, compounds reported to release histamine from cells and thereby leading to arrhythmias in humans, namely morphine, ketamine, and fentanyl, failed to induce a more pronounced positive inotropic effect in atrial preparations from H2-TG compared to WT, arguing against an involvement of histamine release in their proarrhythmic side effects in patients. Measuring left ventricular contractility in isolated retrogradely perfused hearts (Langendorff mode), we detected under basal conditions (no drug application) more spontaneous arrhythmias in hearts from H2-TG than from WT. In summary, we noted that overexpression of human H2-histamine receptors in a novel transgenic animal model can lead to arrhythmias. We suggest that this model might be useful to understand the mechanism(s) of histamine-induced cardiac arrhythmias in humans better in a molecular way and may be of value to screen novel antiarrhythmic drugs.

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“…Drugs like Famotidine (tradename; Pepcid) are histamine receptor antagonists that are routinely used to treat, and prevent certain types ulcers, and to treat conditions that cause the stomach to produce too much acid, and also to treat gastroesophageal reflux disease condition. Clinical evidence of the role of histamine in heart has been well documented, and histamine receptor antagonist in hypertension are cardioprotective [15][16][17]. Interestingly, HCQ is unique in the sense that, at low doses, it mitigates or blunts both the virus's direct effects, as well as the immune reaction/response.…”

Section: Introductionmentioning

confidence: 99%

Multi-organ damage by covid-19: congestive (cardio-pulmonary) heart failure, and blood-heart barrier leakage

Tyagi

Singh

2021

Mol Cell Biochem

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is caused by a coronavirus that is also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and is generally characterized by fever, respiratory inflammation, and multi-organ failure in susceptible hosts. One of the first things during inflammation is the response by acute phase proteins coupled with coagulation. The angiotensinogen (a substrate for hypertension) is one such acute phase protein and goes on to explain an association of covid-19 with that of angiotensin-converting enzyme-2 (ACE2, a metallopeptidase). Therefore, it is advisable to administer, and test the efficacy of specific blocker(s) of angiotensinogen such as siRNAs or antibodies to covid-19 subjects. Covid-19 activates neutrophils, macrophages, but decreases T-helper cells activity. The metalloproteinases promote the activation of these inflammatory immune cells, therefore; we surmise that doxycycline (a metalloproteinase inhibitor, and a safer antibiotic) would benefit the covid-19 subjects. Along these lines, an anti-acid has also been suggested for mitigation of the covid-19 complications. Interestingly, there are three primary vegetables (celery, carrot, and long-squash) which are alkaline in their pH-range as compared to many others. Hence, treatment with fresh juice (without any preservative) from these vegies or the antioxidants derived from purple carrot and cabbage together with appropriate anti-coagulants may also help prevent or lessen the detrimental effects of the covid-19 pathological outcomes. These suggested remedies might be included in the list of putative interventions that are currently being investigated towards mitigating the multi-organ damage by Covid-19 during the ongoing pandemic.

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Characterization of Stressed Transgenic Mice Overexpressing H₂-Histamine Receptors in the Heart

Cited by 25 publications

References 41 publications

Influence of Serotonin 5-HT4 Receptors on Responses to Cardiac Stressors in Transgenic Mouse Models

Influence of Serotonin 5-HT4 Receptors on Responses to Cardiac Stressors in Transgenic Mouse Models

Human histamine H2 receptors can initiate cardiac arrhythmias in a transgenic mouse

Multi-organ damage by covid-19: congestive (cardio-pulmonary) heart failure, and blood-heart barrier leakage

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Characterization of Stressed Transgenic Mice Overexpressing H2-Histamine Receptors in the Heart

Cited by 25 publications

References 41 publications

Influence of Serotonin 5-HT4 Receptors on Responses to Cardiac Stressors in Transgenic Mouse Models

Influence of Serotonin 5-HT4 Receptors on Responses to Cardiac Stressors in Transgenic Mouse Models

Human histamine H2 receptors can initiate cardiac arrhythmias in a transgenic mouse

Multi-organ damage by covid-19: congestive (cardio-pulmonary) heart failure, and blood-heart barrier leakage

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Characterization of Stressed Transgenic Mice Overexpressing H₂-Histamine Receptors in the Heart