Angiotensin-(1–9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway

Sotomayor-Flores, Cristian; Rivera-Mejías, Pablo; Vásquez‐Trincado, César; López-Crisosto, Camila; Morales, Pablo E.; Pennanen, Christian; Polakovičová, Iva; Aliaga-Tobar, Víctor; Garcı́a, Lorena; Roa, Juan Carlos; Rothermel, Beverly A.; Maracaja-Coutinho, Vinícius; Ho-Xuan, Hung; Meister, Gunter; Chiong, Mario; Ocaranza, María Paz; Corvalán, Alejandro; Parra, Valentina; Lavandero, Sergio

doi:10.1038/s41418-020-0522-3

Cited by 35 publications

(29 citation statements)

References 77 publications

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“…While PKI peptides have been extensively used to study PKA function, our study highlights the importance of understanding the biological consequences of altered PKI protein expression on downstream cAMP signaling. PKI protein levels regulate glucose homeostasis, 59 cardiomyocyte hypertrophy, 60 neuronal potentiation, 61 and morphine antinociceptive tolerance. 19 Further evidence also suggests PKI proteins may dysregulate signaling programs and cell fate F I G U R E 8 PKI acts as a molecular switch downstream of GPCR-Gαs signaling.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase A inhibitor proteins (PKIs) divert GPCR‐Gαs‐cAMP signaling toward EPAC and ERK activation and are involved in tumor growth

et al. 2020

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The PKA‐inhibitor (PKI) family members PKIα, PKIβ, and PKIγ bind with high affinity to PKA and block its kinase activity, modulating the extent, and duration of PKA‐mediated signaling events. While PKA is a well‐known regulator of physiological and oncogenic events, the role of PKI proteins in these pathways has remained elusive. Here, by measuring activation of the MAPK pathway downstream of GPCR‐Gαs‐cAMP signaling, we show that the expression levels of PKI proteins can alter the balance of activation of two major cAMP targets: PKA and EPAC. Our results indicate that PKA maintains repressive control over MAPK signaling as well as a negative feedback on cAMP concentration. Overexpression of PKI and its subsequent repression of PKA dysregulates these signaling pathways, resulting in increased intracellular cAMP, and enhanced activation of EPAC and MAPK. We also find that amplifications of PKIA are common in prostate cancer and are associated with reduced progression free survival. Depletion of PKIA in prostate cancer cells leads to reduced migration, increased sensitivity to anoikis and reduced tumor growth. By altering PKA activity PKI can act as a molecular switch, driving GPCR‐Gαs‐cAMP signaling toward activation of EPAC‐RAP1 and MAPK, ultimately modulating tumor growth.

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Section: Discussionmentioning

confidence: 99%

Protein kinase A inhibitor proteins (PKIs) divert GPCR‐Gαs‐cAMP signaling toward EPAC and ERK activation and are involved in tumor growth

et al. 2020

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“…Critically, mitochondria have a functional angiotensin system [ 85 ], and ACE2 seems to be mitochondrially protective [ 86 ]. Potentially of interest here is that a product of ACE2, angiotensin-(1–9), seems to inhibit mitochondrial fission in the heart, enhancing mitochondrial fusion and calcium buffering and protecting against cardiac hypertrophy [ 87 ]. It is thus possible, by binding to ACE2, the virus may suppress a counter-balancing anti-inflammatory pathway that affects mitochondrial function.…”

Section: Does Sars-cov-2 Modulate Mitochondrial Function Either Indimentioning

confidence: 99%

SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing

Nunn

Guy²,

Brysch

et al. 2020

Immun Ageing

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Infection with SARs-COV-2 displays increasing fatality with age and underlying co-morbidity, in particular, with markers of the metabolic syndrome and diabetes, which seems to be associated with a “cytokine storm” and an altered immune response. This suggests that a key contributory factor could be immunosenescence that is both age-related and lifestyle-induced. As the immune system itself is heavily reliant on mitochondrial function, then maintaining a healthy mitochondrial system may play a key role in resisting the virus, both directly, and indirectly by ensuring a good vaccine response. Furthermore, as viruses in general, and quite possibly this new virus, have also evolved to modulate immunometabolism and thus mitochondrial function to ensure their replication, this could further stress cellular bioenergetics. Unlike most sedentary modern humans, one of the natural hosts for the virus, the bat, has to “exercise” regularly to find food, which continually provides a powerful adaptive stimulus to maintain functional muscle and mitochondria. In effect the bat is exposed to regular hormetic stimuli, which could provide clues on how to resist this virus. In this paper we review the data that might support the idea that mitochondrial health, induced by a healthy lifestyle, could be a key factor in resisting the virus, and for those people who are perhaps not in optimal health, treatments that could support mitochondrial function might be pivotal to their long-term recovery.

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“…This cleavage results in an increase of the vasoconstrictor activity of angiotensin, whose activated form is known as angiotensin II (Ang II). The counter-regulatory carboxypeptidase angiotensin-converting enzyme 2 (ACE2) catalyzes the irreversible conversion of angiotensin I to angiotensin 1-9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes (Sotomayor-Flores et al 2020), and angiotensin II to angiotensin 1-7, which is a potent vasodilator. ACE2 is, therefore, a fundamental regulator of blood volume, vascular resistance, and cardiovascular homeostasis (Jia 2016, Kreutz et al 2020.…”

Section: Pathogenic Mechanisms Of the New Coronoavirus And Their Consmentioning

confidence: 99%

Hemostatic abnormalities in COVID-19: A guided review

Sathler

2020

An. Acad. Bras. Ciênc.

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The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already taken on pandemic proportions, affecting over 213 countries in a matter of weeks. In this context, several studies correlating hemostatic disorders with the infection dynamics of the new coronavirus have emerged. These studies have shown that a portion of the patients affected by Coronavirus Disease 2019 (COVID-19) have prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), elevated D-dimer levels and other fi brinolytic products, antithrombin (AT) activity reduced and decrease of platelet count. Based on these hallmarks, this review proposes to present possible pathophysiological mechanisms involved in the hemostatic changes observed in the pathological progression of COVID-19. In this analysis, it is pointed the relationship between the downregulation of angiotensin-converting enzyme 2 (ACE2) and storm cytokines action with the onset of hypercoagulability state, other than the clinical events involved in thrombocytopenia and hyperfi brinolysis progression.

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Angiotensin-(1–9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway

Cited by 35 publications

References 77 publications

Protein kinase A inhibitor proteins (PKIs) divert GPCR‐Gαs‐cAMP signaling toward EPAC and ERK activation and are involved in tumor growth

Protein kinase A inhibitor proteins (PKIs) divert GPCR‐Gαs‐cAMP signaling toward EPAC and ERK activation and are involved in tumor growth

SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing

Hemostatic abnormalities in COVID-19: A guided review

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