Effects of direct pharmacological Gq protein modulation on lung and right heart remodeling

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G proteins are important modulators of (patho-)physiological functions in many organ systems. In the lung, the Gq subtype is of particular relevance, as it is a key mediator of smooth muscle tone in both, airways and pulmonary arteries. This signaling pathway is also involved in chronic lung diseases such as asthma and pulmonary hypertension. Therefore a selective pan-Gq inhibitor would help to gain better insight into the (patho-)physiological role of Gq proteins and could even provide novel therapeutic options. In the current proposal we will investigate the effect of the pharmacological Gq inhibitor FR900359 provided by the consortium in regard to its potential to reduce airway and vascular tone in the lung. To this end we will pursue in vitro, ex vivo and in vivo approaches in mouse and murine, porcine and human tissue. We will compare the effects of the pharmacological Gq inhibitor on airway and vessel function with that in cells and tissues of genetic Gq deficiency in order to mechanistically understand the individual physiological role of Gq subtypes. Finally, we will examine the potential of the pharmacological Gq inhibitor to reduce airway and vascular tone in mouse models of asthma and pulmonary hypertension. We will also test different application routes such as inhalation of the compound to minimize systemic side effects in vivo. Thus, our studies are expected to provide novel insights into the mechanistic role of Gq proteins in tone regulation in the lung and into the therapeutic potential of Gq protein inhibition in lung disease.