Left ventricular hypertrophy (LVH) is a major contributor to the development of heart failure (HF). Alterations in cyclic adenosine monophosphate (cAMP)-dependent signaling pathways participate in cardiomyocyte hypertrophy and mitochondrial dysfunction occurring in LVH and HF. cAMP signals are received and integrated by a family of cAMP-dependent protein kinase A (PKA) anchor proteins (AKAPs), tethering PKA to discrete cellular locations. AKAPs encoded by the Akap1 gene (mitoAKAPs) promote PKA mitochondrial targeting, regulating mitochondrial structure and function, reactive oxygen species production, and cell survival. To determine the role of mitoAKAPs in LVH development, in the present investigation, mice with global genetic deletion of Akap1 (Akap1-/-), Akap1 heterozygous (Akap1+/-), and their wild-type (wt) littermates underwent transverse aortic constriction (TAC) or SHAM procedure for 1 week. In wt mice, pressure overload induced the downregulation of AKAP121, the major cardiac mitoAKAP. Compared to wt, Akap1-/- mice did not display basal alterations in cardiac structure or function and cardiomyocyte size or fibrosis. However, loss of Akap1 exacerbated LVH and cardiomyocyte hypertrophy induced by pressure overload and accelerated the progression toward HF in TAC mice, and these changes were not observed upon prevention of AKAP121 degradation in seven in absentia homolog 2 (Siah2) knockout mice (Siah2-/-). Loss of Akap1 was also associated to a significant increase in cardiac apoptosis as well as lack of activation of Akt signaling after pressure overload. Taken together, these results demonstrate that in vivo genetic deletion of Akap1 enhances LVH development and accelerates pressure overload-induced cardiac dysfunction, pointing at Akap1 as a novel repressor of pathological LVH. These results confirm and extend the important role of mitoAKAPs in cardiac response to stress.

Accumulating evidence suggests that modifications of gut function and microbiota composition might play a pivotal role in the pathophysiology of several cardiovascular diseases, including heart failure (HF). In this study we systematically analysed gut microbiota composition, intestinal barrier integrity, intestinal and serum cytokines and serum endotoxin levels in C57BL/6 mice undergoing pressure overload by transverse aortic constriction (TAC) for 1 and 4 weeks. Compared to sham-operated animals, TAC induced prompt and strong weakening of intestinal barrier integrity, long-lasting decrease of colon anti-inflammatory cytokine levels, significant increases of serum levels of bacterial lipopolysaccharide and proinflammatory cytokines. TAC also exerted effects on microbiota composition, inducing significant differences in bacterial genera inside Actinobacteria, Firmicutes, Proteobacteria and TM7 phyla as shown by 16S rDNA sequencing of fecal samples from TAC or sham mice. These results suggest that gut modifications represent an important element to be considered in the development and progression of cardiac dysfunction in response to TAC and support this animal model as a valuable tool to establish the role and mechanisms of gut-heart crosstalk in HF. Evidence arising in this field might identify new treatment options targeting gut integrity and microbiota components to face adverse cardiac events.

Background Microbiota composition plays an important role in the pathophysiology of heart failure (HF). Reduced cardiac output can disrupt intestinal barrier function and promote systemic inflammation through bacterial translocation. Several gut and cardiac pathological conditions are reciprocally linked at multiple levels and through different, still largely undefined mechanisms. Purpose We analyzed the effects of Transverse aortic constriction (TAC) on aortic pressures, gut barrier integrity, systemic inflammation and gut microbiota composition. Methods TAC was induced in C57BL6 mice of either sex. Sham-operated (Sham) mice were used as controls. After one-week (1w) and four weeks (4w), mice have been anesthetized, cardiac function and abdominal aortic blood flow were analyzed. Colon, serum and feces samples were collected after sacrifice. Intestinal barrier integrity was evaluated in colon samples by Tight junction protein ZO-1 (Tjp1) and Occludin (Ocln) mRNA analysis. Circulating levels of Tumor Necrosis Factor-alpha (TNF-alpha), Lipopolysaccharide (LPS), Interleukin-10 and Interleukin-1 were measured. Microbial DNA was extracted from feces samples and gut microbiota composition was evaluated by Illumina Mi-Seq analysis. Results TAC induced left ventricular hypertrophy and systolic dysfunction. Abdominal aortic blood flow was significantly reduced in TAC mice compared to sham (Figure 1A). Decreased intestinal perfusion in TAC mice was associated to a prompt and strong weakening of intestinal barrier integrity and long-lasting decrease of colonic anti-inflammatory cytokine levels, as shown by reduced mRNA expression of interleukin-10 (IL-10) and Occludin (Ocln) (Figure 1B). Serum levels of lipopolysaccharide (LPS) were increased after TAC surgery and significant increases of circulating proinflammatory cytokines tumor necrosis factor-a (TNF-a) were detected in TAC mice (Figure 1C). High-resolution approach was used to obtain bacterial species assignment of key genera with significant differences among groups. After TAC, significant increases of Bifidobacterium, Lactobacillus and Turicibacter, whereas the genus Oscillospira was significantly less (Figure 1D). Butyrate-producing bacteria are considered relevant colonizers of the gastrointestinal tract being butyrate important in anti-inflammation and maintaining intestinal barrier integrity. Oscillospira genus members have been described as butyrate producers. Notably, in old patients with heart failure and in animal models of hypertension, increase in lactate-producing Lactobacillus was found. Conclusions These data indicate a remodeling of specific bacterial species abundance within identified key genera starting soon after TAC, designating a clear effect of the treatment on microbiota profiles and, possibly, on microbiota functionality. Gut dysbiosis may represent an element to be considered in the development or progression of cardiac dysfunction. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): CP was supported by Ministero dell'Istruzione, Università e Ricerca Scientifica grant (2015583WMX) and Programma STAR grant by Federico II University and Compagnia di San Paolo. RP was supported by a research grant provided by the Cardiopath PhD program. LC was supported by 2018-2019 Postdoctoral Fellowship Grants provided by Fondazione Umberto Veronesi.

Second messenger cyclic adenosine monophosphate (cAMP) has been found to regulate multiple mitochondrial functions, including respiration, dynamics, reactive oxygen species production, cell survival and death through the activation of cAMP-dependent protein kinase A (PKA) and other effectors. Several members of the large family of A kinase anchor proteins (AKAPs) have been previously shown to locally amplify cAMP/PKA signaling to mitochondria, promoting the assembly of signalosomes, regulating multiple cardiac functions under both physiological and pathological conditions. In this review, we will discuss roles and regulation of major mitochondria-targeted AKAPs, along with opportunities and challenges to modulate their functions for translational purposes in the cardiovascular system.

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