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.