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

Abstract

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.

Correlation Analysis of Blood Glucose Level with Inflammatory Response and Immune Indicators in Patients with Sepsis

“…In the present study, the lowest immune function indicators CD4+ and CD8+ levels were found in the observation group, followed by the experimental group, and then the control group ( P < 0.05), suggesting that patients with sepsis are associated with abnormal expression levels of T lymphocytes, which underscores the role of the assay of CD4+ and CD8+ levels for early diagnosis and treatment of sepsis. Moreover, the blood glucose level of patients with sepsis was positively correlated with the levels of IL-6, TNF- α and IL-1 β and was negatively correlated with the levels of CD4+/CD8+; the higher the blood glucose, the lower the number of immune cells, which is in line with the results of the report by Nakamura et al [ 24 ], indicating that the high blood glucose levels are associated with more severe immunity dysfunction in the patients with sepsis. As blood sugar levels increase, IL-6, TNF- α and IL-1 β levels present a trend of increase, whereas the level of CD4+/CD8+ shows a downward trend.…”

Temperature alters the inotropic, chronotropic and proarrhythmic effects of histamine in atrial muscle preparations from humans and H2-receptor overexpressing mice

“…This was the reason why we have generated H 2 -TG: to study histamine and its action on human H 2 -receptors in a mammalian transgenic heart: only in H 2 -TG but not in WT, histamine exerts a positive inotropic effect. We have confirmed this finding repeatedly (Gergs et al 2019a , b , 2020 ; Neumann et al 2021a , b , c ). As concerns the biochemical basis for these contractile studies, we detected endogenous mouse H 2 -receptors by polymerase chain reaction (PCR) in hearts from WT (Neumann et al 2021c ).…”

“…1 ). We noted in left atrial preparations from WT that isoproterenol tended to be less potent to raise force of contraction at 23 °C than at 37 °C (Gergs et al 2021a , b , c , d ). Similarly, the effect of histamine on force of contraction in H 2 -TG at 23 °C is located to the right of the curve at 37 °C (Fig.…”

“…Western blots were done without success (discussed in Gergs et al a , 2019b ): with the commercially available antibodies, we detected only unspecific signals. However, we could detect H 2 -receptors by autoradiography in atria (and ventricles) from H 2 -TG using a radioactive tracer (Gergs et al 2019a , b ) (Table 1 ).…”

Mechanisms of Systolic Cardiac Dysfunction in PP2A, PP5 and PP2AxPP5 Double Transgenic Mice

“…Interestingly, RNA and protein overexpression of PP2Ac and PP5 are lower in DT than in monotransgenic PP2A or monotransgenic PP5 mice. This effect can be assumed to be specific because in a different double transgenic model, the PP2A mice were crossbred with 5-HT 4 receptor overexpressing mice and in these double transgenic mice, PP2A expression was unchanged compared to the monotransgenic PP2A mice [75]. Hence, some interesting interaction could exist.…”