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

• Main Authors: Ulrich Gergs, Timo Gerigk, Jonas Wittschier, Constanze T. Schmidbaur, Clara Röttger, Mareen Mahnkopf, Hanna Edler, Hartmut Wache, Joachim Neumann
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Biomedicines
• Subjects: serotonin; LPS; hypoxia; ischemia; PP2A transgenic mice; inflammation
• Online Access: https://www.mdpi.com/2227-9059/9/5/569

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-HT_4a 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.