Antagonistic modulation of SIK1 and SIK2 isoforms in high blood pressure and cardiac hypertrophy triggered by high-salt intake

Pires, Nuno; Igreja, Bruno; Soares-da-Silva, Patrı́cio

doi:10.1080/10641963.2021.1896728

Cited by 7 publications

(5 citation statements)

References 15 publications

(27 reference statements)

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“…Sik2 deletion does not affect the BP but prevents the development of left ventricular hypertrophy (LVH) on chronic HS intake ( Popov et al, 2014 ). Instead, combined Sik1/2 deletion leads to higher BP but does not alter LVH on chronic HS intake, suggesting that SIK1 is required for maintaining normal BP while SIK2 is required for HS-induced cardiac hypertrophy independent of high BP ( Pires et al, 2021 ). Further evidence also supports a pathological role for SIK2 in cardiac hypertrophy.…”

Section: Sodium Sensing and Salt Intakementioning

confidence: 99%

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Understanding the roles of salt-inducible kinases in cardiometabolic disease

Shi

2024

Front. Physiol.

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Salt-inducible kinases (SIKs) are serine/threonine kinases of the adenosine monophosphate-activated protein kinase family. Acting as mediators of a broad array of neuronal and hormonal signaling pathways, SIKs play diverse roles in many physiological and pathological processes. Phosphorylation by the upstream kinase liver kinase B1 is required for SIK activation, while phosphorylation by protein kinase A induces the binding of 14-3-3 protein and leads to SIK inhibition. SIKs are subjected to auto-phosphorylation regulation and their activity can also be modulated by Ca2+/calmodulin-dependent protein kinase in response to cellular calcium influx. SIKs regulate the physiological processes through direct phosphorylation on various substrates, which include class IIa histone deacetylases, cAMP-regulated transcriptional coactivators, phosphatase methylesterase-1, among others. Accumulative body of studies have demonstrated that SIKs are important regulators of the cardiovascular system, including early works establishing their roles in sodium sensing and vascular homeostasis and recent progress in pulmonary arterial hypertension and pathological cardiac remodeling. SIKs also regulate inflammation, fibrosis, and metabolic homeostasis, which are essential pathological underpinnings of cardiovascular disease. The development of small molecule SIK inhibitors provides the translational opportunity to explore their potential as therapeutic targets for treating cardiometabolic disease in the future.

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Section: Sodium Sensing and Salt Intakementioning

confidence: 99%

“…In contrast, SIK2 activation has been implicated in cardiac hypertrophy. SIK2 deletion prevents HS-induced cardiac hypertrophy independent of high BP ( Pires et al, 2021 ). In hypertensive Milan rats, the hypertensive variant of α-adducin is associated with higher Sik2 expression and LVH ( Popov et al, 2014 ).…”

Section: Cardiac Hypertrophy and Ischemiamentioning

confidence: 99%

Understanding the roles of salt-inducible kinases in cardiometabolic disease

Shi

2024

Front. Physiol.

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“…In contrast, SIK2 KO mice do not show increases in BP in response to a high-salt diet or changes in plasma Na + and K + levels but display cardiac hypertrophy in response to high-salt intake ( 124 ). Double knockouts have led to further confounding results; SIK1/2 double knockout mice surprisingly show an increase in blood pressure but no hypertrophy ( 125 ). Furthermore, the modulation of Na + -K + -ATPase activity in renal proximal tubules in the kidney by SIK (primarily SIK1) is responsible for sodium reabsorption; thus SIK1-KO mice but not SIK2 KO display increased natriuresis ( 121 , 124 ).…”

Section: The Physiological Roles Of Salt-inducible Kinasesmentioning

confidence: 99%

The multiple roles of salt-inducible kinases in regulating physiology

Jagannath

Taylor

et al. 2023

Physiological Reviews

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Salt-Inducible kinases, which comprise a family of three homologous serine-threonine kinases were first described for their role in sodium sensing, but have since been shown to regulate multiple aspects of physiology. These kinases are activated or deactivated in response to extracellular signals that are cell surface receptor mediated, and go on to phosphorylate multiple targets including the transcription co-factors CRTC1-3 and the Class IIa histone deacetylases (HDACs). Thus, the SIK family conveys signals about the cellular environment to reprogram transcriptional and post-transcriptional processes in response. In this manner, SIKs have been shown to regulate metabolic responses to feeding/fasting, cell division and oncogenesis, inflammation, and immune responses and most recently, sleep and circadian rhythms. Sleep and circadian rhythms are master regulators of physiology and are exquisitely sensitive to regulation by environmental light, and physiological signals such as need for sleep. Salt-Inducible kinases have been shown to be central the molecular control of both these processes. Here we summarise the molecular mechanisms by which SIKs control these different domains of physiology and highlight where there is mechanistic overlap with sleep/circadian rhythm control.

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“…Consequently, SIK1 appears to have a minor contribution to the activity in immune cells. In contrast, SIK1 was reported to play a key role in blood pressure regulation and vascular remodeling. − Dual SIK2/SIK3 inhibition with selectivity against SIK1 could therefore offer a better safety profile with a lower impact on the cardiovascular system than pan-SIK inhibition, while retaining the desired activity on the immune system.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases

Peixoto,

Joncour,

Temal-Laib

et al. 2024

J. Med. Chem.

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The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (32), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC 50 of 282.8 nM on SIK1, 7.8 nM on SIK2 and 3.8 nM on SIK3). We outline efforts made to increase selectivity against SIK1 and improve CYP time-dependent inhibition properties through the structure−activity relationship. The dual activity of 32 in modulating the pro-inflammatory cytokine TNFα and the immunoregulatory cytokine IL-10 is demonstrated in vitro in human primary myeloid cells and human whole blood, and in vivo in mice stimulated with lipopolysaccharide. Compound 32 shows dose-dependent activity in disease-relevant mouse pharmacological models.

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Antagonistic modulation of SIK1 and SIK2 isoforms in high blood pressure and cardiac hypertrophy triggered by high-salt intake

Abstract: Soares-da-Silva (2021): Antagonistic modulation of SIK1 and SIK2 isoforms in high blood pressure and cardiac hypertrophy triggered by high-salt intake, Clinical and Experimental Hypertension,

Cited by 7 publications

References 15 publications

Understanding the roles of salt-inducible kinases in cardiometabolic disease

Understanding the roles of salt-inducible kinases in cardiometabolic disease

The multiple roles of salt-inducible kinases in regulating physiology

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases

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