Abstract
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.
Highlights
Pathological left ventricular hypertrophy (LVH) is a hallmark feature of a number cardiovascular diseases (Hill and Olson, 2008; Schiattarella and Hill, 2015; Schiattarella et al, 2017) and is strongly associated with increased risk of developing heart failure (HF; Levy et al, 1990)
We have previously demonstrated that myocardial levels of AKAP121 decrease in a rat model of LVH induced by ascending aortic banding (Perrino et al, 2010), suggesting a role for this adaptor protein in the transmission of hypertrophic signals in the myocardium
Consistent with our previous results, AKAP121 cardiac levels were significantly decreased in wt mice subjected to 1w transverse aortic constriction (TAC) compared to sham-operated littermates (Figure 1A), and these results were associated with the impairment of mitochondrial protein kinase A (PKA) signaling (Supplementary Figure S1)
Summary
Pathological left ventricular hypertrophy (LVH) is a hallmark feature of a number cardiovascular diseases (Hill and Olson, 2008; Schiattarella and Hill, 2015; Schiattarella et al, 2017) and is strongly associated with increased risk of developing heart failure (HF; Levy et al, 1990). Despite the critical role of LVH in the development of cardiac dysfunction, the mechanisms underlying cardiomyocyte hypertrophy in response to pressure overload still remain not completely understood. Members of a family of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) anchor proteins (AKAPs) have been identified as potential regulators of cardiac responses to pathological stimuli including pressure overloadinduced LVH (Perrino et al, 2010; Diviani et al, 2011; Rababa’h et al, 2014). MAKAP has been shown to regulate hypertrophy of neonatal cardiomyocytes through mitogen-activated protein kinases (MAPKs) signaling pathways (Rababa’h et al, 2014). AKAP-Lbc regulates cardiomyocytes hypertrophy forming a complex with other protein kinases (Carnegie et al, 2008)
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