D'Apice, Stefania (2023) Role of mitochondrial AKAPs and heart-gut axis in cardiovascular diseases. [Tesi di dottorato]

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Abstract

Cardiovascular disease (CVD) is the leading cause of mortality, morbidity, and hospitalization in industrialized countries. Continuous scientific progress is essential for understanding the molecular, pathophysiological, and adaptive mechanisms underlying the development of CVD. Knowledge of these processes is fundamental to optimize the therapeutic approach, identify new potential drug targets and improve the quality of life of patients affected by CVD. Mitochondrial dysfunction, in cardiomyocyte, is among the earliest and most common molecular alterations detected in numerous CVD, frequently associated with an increase in cellular oxidative stress. Second messenger cyclic adenosine monophosphate (cAMP) is a crucial regulator of mitochondrial function, involved in mitochondrial respiration, dynamics, reactive oxygen species (ROS) production, cell survival and death through the activation of cAMP-dependent protein kinase A (PKA). Several members of the large family of mitochondria A kinase anchor proteins (mitochondrial AKAPs) locally amplify cAMP/PKA signaling to mitochondria, regulating cardiac functions under both physiological and pathological conditions. Therefore, mitochondrial AKAPs might represent novel therapeutic molecular targets for CVD. Mounting evidence suggests that mitochondrial dysfunction and oxidative stress play a role in changes in gut barrier function and gut microbiota composition. Recent studies have shown that several interactions exist between intestinal microbiota and the cardiovascular system, mediated by numerous and various mechanisms. On the one hand, the gut microbiota and the related metabolites produced can modulate the function and survival of cardiomyocytes and other cardiac cell populations, under physiological or pathological conditions. On the other hand, numerous studies demonstrate that the hemodynamic changes resulting from CVD can induce profound abnormalities of gut permeability and gut microbiota composition5. This evidence suggests the existence of a crosstalk between gut and the heart, even if the mechanisms and mediators remain unclear.

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