Regulation of Cardiac PKA Signaling by cAMP and Oxidants

Cuello, Friederike; Herberg, Friedrich W.; Σταθοπούλου, Κωνσταντίνα; Henning, Philipp; Diering, Simon

doi:10.3390/antiox10050663

Cited by 6 publications

(5 citation statements)

References 215 publications

(303 reference statements)

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“…PKA is the primary effector of cAMP signaling and a direct upstream regulator of LKB1 ( Collins et al, 2000 ). In the heart, PKA becomes activated when β-adrenoceptors on the surface of cardiomyocytes transduce various neurohumoral and mechanical stress signals, resulting in the production of cAMP ( Cuello et al, 2021 ). Activated PKA phosphorylates LKB1 at Ser 431; once activated, LKB1 phosphorylates AMPKα at Thr 172 within its catalytic subunit, leading to AMPK-mediated inhibition of mTORC1 and AAC activity ( Huang et al, 2019 ; Kari et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Liquiritin Attenuates Pathological Cardiac Hypertrophy by Activating the PKA/LKB1/AMPK Pathway

et al. 2022

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Background: Liquiritin (LQ) is one of the main flavonoids extracted from the roots of Glycyrrhiza spp., which are widely used in traditional Chinese medicine. Studies in both cellular and animal disease models have shown that LQ attenuates or prevents oxidative stress, inflammation, and apoptosis. However, the potential therapeutic effects of LQ on pressure overload-induced cardiac hypertrophy have not been so far explored. Therefore, we investigated the cardioprotective role of LQ and its underlying mechanisms in the aortic banding (AB)-induced cardiac hypertrophy mouse model.Methods and Results: Starting 3 days after AB surgery, LQ (80 mg/kg/day) was administered daily over 4 weeks. Echocardiography and pressure-volume loop analysis indicated that LQ treatment markedly improved hypertrophy-related cardiac dysfunction. Moreover, hematoxylin and eosin, picrosirius red, and TUNEL staining showed that LQ significantly inhibited cardiomyocyte hypertrophy, interstitial fibrosis, and apoptosis. Western blot assays further showed that LQ activated LKB1/AMPKα2/ACC signaling and inhibited mTORC1 phosphorylation in cardiomyocytes. Notably, LQ treatment failed to prevent cardiac dysfunction, hypertrophy, and fibrosis in AMPKα2 knockout (AMPKα2−/−) mice. However, LQ still induced LKB1 phosphorylation in AMPKα2−/− mouse hearts. In vitro experiments further demonstrated that LQ inhibited Ang II-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) by increasing cAMP levels and PKA activity. Supporting the central involvement of the cAMP/PKA/LKB1/AMPKα2 signaling pathway in the cardioprotective effects of LQ, inhibition of Ang II-induced hypertrophy and induction of LKB1 and AMPKα phosphorylation were no longer observed after inhibiting PKA activity.Conclusion: This study revealed that LQ alleviates pressure overload-induced cardiac hypertrophy in vivo and inhibits Ang II-induced cardiomyocyte hypertrophy in vitro via activating cAMP/PKA/LKB1/AMPKα2 signaling. These findings suggest that LQ might be a valuable adjunct to therapeutic approaches for treating pathological cardiac remodeling.

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Section: Discussionmentioning

confidence: 99%

Liquiritin Attenuates Pathological Cardiac Hypertrophy by Activating the PKA/LKB1/AMPK Pathway

et al. 2022

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“…According to Bang and Zippin [ 73 ], cAMP is a second messenger that regulates numerous functions in both benign melanocytes and melanoma cells. In animals, an alpha-melanocyte-stimulating hormone (alpha-MSH) and an adrenocorticotropic hormone (ACTH) are primarily responsible for pigmentation [ 74 ]. Significant pathways such as MAPK signaling and oxidative stress response pathways were identified in both herds.…”

Section: Discussionmentioning

confidence: 99%

Linkage Disequilibrium, Haplotype Block Structures, Effective Population Size and Genome-Wide Signatures of Selection of Two Conservation Herds of the South African Nguni Cattle

Dlamini

Dzomba

Magawana

et al. 2022

Animals

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The Nguni cattle of South Africa are a Sanga breed, characterized by many eco-types and research populations that have been established in an effort to conserve the diversity within the breed. The aim of this study was to investigate the overall genetic diversity as well as similarities and differences within and between two conservation herds of the South African Nguni Cattle. Mean LD (r2) estimates were 0.413 ± 0.219 for Bartlow Combine and 0.402 ± 0.209 for Kokstad. Genome-wide average LD (r2) decreased with increasing genetic marker distance for both populations from an average of 0.76 ± 0.28 and 0.77 ± 0.27 at 0–1 kb bin to 0.31 ± 0.13 and 0.32 ± 0.13 at 900–1000 kb bin in Bartlow Combine and Kokstad populations, respectively. Variation in LD levels across autosomes was observed in both populations. The results showed higher levels of LD than previously reported in Nguni field populations and other South African breeds, especially at shorter marker distances of less than 20 kb. A total number of 77,305 and 66,237 haplotype blocks covering a total of 1570.09 Mb (61.99% genome coverage) and 1367.42 Mb (53.96% genome coverage) were detected in Bartlow Combine and Kokstad populations, respectively. A total of 18,449 haploblocks were shared between the two populations while 58,856 and 47,788 haploblocks were unique to Bartlow Combine and Kokstad populations, respectively. Effective population size (Ne) results demonstrated a rapid decrease in Ne across generations for both Bartlow Combine and Kokstad conservation herds. Two complementary methods, integrated haplotype score (iHS) and Extend Haplotype Homozygosity Test (XP-EHH), were implemented in this study to detect the selection signatures in the two herds. A total of 553 and 166 selected regions were identified in Bartlow Combine and Kokstad populations, respectively. DAVID and GO terms analysis of the regions under selection reported genes/QTLs associated with fertility, carcass weight, coat colour, immune response, and eye area pigmentation. Some genes, such as HCAR1, GNAI1, PIK3R3, WNT3, RAB5A, BOLA-N (Class IB MHC Antigen QA-2-Related), BOLA (Class IB MHC Antigen QA-2-Related), and Rab-8B, etc., were found in regions under selection in this study. Overall, the study implied reduced genetic diversity in the two herds calling for corrective measures to maintain the diversity of the South African Nguni cattle. This study presented a comprehensive analysis of the genomic architecture of South African Nguni cattle populations, providing essential genetic information of utility in the management of conservation flocks.

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“…We also found a significant increase in site specific phosphorylation of cMyBP-C at Ser 282 that occurred in the Tm-180 filaments and was reduced substantially with NAC. These results indicate that levels of sarcomere protein phosphorylation may be directly affected by alterations of Cys residues by S-glutathionylation, but the net effects may also depend on oxidative stress effects on kinase/phosphatase pathways ( 70 ).…”

Section: Avenues Of Future Research In Cardiac Physiology and Pathologymentioning

confidence: 99%

Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis

Rosas¹,

Solaro

2023

Front. Cardiovasc. Med.

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The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic dysfunction led to new concepts regarding how levels of oxidative stress affect the heartbeat. Major sarcomere proteins for which there is evidence of S-glutathionylation include cardiac myosin binding protein C (cMyBP-C), actin, cardiac troponin I (cTnI) and titin. Our hypothesis is that these S-glutathionylated proteins are significant factors in acquired and familial disorders of the heart; and, when released into the serum, provide novel biomarkers. We consider the molecular mechanisms for these effects in the context of recent revelations of how these proteins control cardiac dynamics in close collaboration with Ca2+ fluxes. These revelations were made using powerful approaches and technologies that were focused on thin filaments, thick filaments, and titin filaments. Here we integrate their regulatory processes in the sarcomere as modulated mainly by neuro-humoral control of phosphorylation inasmuch evidence indicates that S-glutathionylation and protein phosphorylation, promoting increased dynamics and modifying the Frank-Starling relation, may be mutually exclusive. Earlier studies demonstrated that in addition to cTnI as a well-established biomarker for cardiac disorders, serum levels of cMyBP-C are also a biomarker for cardiac disorders. We describe recent studies approaching the question of whether serum levels of S-glutathionylated-cMyBP-C could be employed as an important clinical tool in patient stratification, early diagnosis in at risk patients before HFpEF, determination of progression, effectiveness of therapeutic approaches, and as a guide in developing future therapies.

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Regulation of Cardiac PKA Signaling by cAMP and Oxidants

Cited by 6 publications

References 215 publications

Liquiritin Attenuates Pathological Cardiac Hypertrophy by Activating the PKA/LKB1/AMPK Pathway

Liquiritin Attenuates Pathological Cardiac Hypertrophy by Activating the PKA/LKB1/AMPK Pathway

Linkage Disequilibrium, Haplotype Block Structures, Effective Population Size and Genome-Wide Signatures of Selection of Two Conservation Herds of the South African Nguni Cattle

Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis

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