PI3Kγ inhibition reduces blood pressure by a vasorelaxant Akt/L-type calcium channel mechanism

Carnevale, Daniela; Vecchione, Carmine; Mascio, Giada; Esposito, Giovanni; Cifelli, Giuseppe; Martinello, Katiuscia; Landolfi, Alessandro; Selvetella, Giulio; Grieco, Paolo; Damato, Antonio L.; Franco, Elio; Haase, Hannelore; Maffei, Angelo; Ciraolo, Elisa; Fucile, Sergio; Frati, Giacomo; Mazzoni, Orazio; Hirsch, Emilio; Lembo, Giuseppe

doi:10.1093/cvr/cvr288

Cited by 45 publications

(49 citation statements)

References 25 publications

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“…PI3K/Akt signaling promoted voltage-dependent trafficking of Ca 2ϩ channels to the plasma membrane that increased Ca 2ϩ influx via L-type VOCC and thereby was involved in the myogenic response in mouse second-order mesenteric arteries (197,910). Genetic knockdown of Dicer for 5-6 wk to reduce the global role of microRNAs (miRNAs) lowered BP and myogenic tone in mesenteric arteries by reducing PI3K/Akt signaling and L-type VOCC activity (specifically the ␣2␦1 subunit) (101).…”

Section: Renal Autoregulatory Mechanismsmentioning

confidence: 99%

Renal Autoregulation in Health and Disease

Carlström

Wilcox

Arendshorst

2015

Physiological Reviews

391

383

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Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80-180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca(2+)]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca(2+)]i occurs predominantly by Ca(2+) influx through L-type voltage-operated Ca(2+) channels (VOCC). Increased [Ca(2+)]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca(2+) from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca(2+) sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study.

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Section: Renal Autoregulatory Mechanismsmentioning

confidence: 99%

Renal Autoregulation in Health and Disease

Carlström

Wilcox

Arendshorst

2015

Physiological Reviews

391

383

View full text Add to dashboard Cite

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“…In the last decade, a consistent piece of literature demonstrated the expression of PI3Kγ in cardiovascular system cells [5,15,16], as vascular smooth muscle cells (VSMCs) [36]. In this regard, it has been shown that PI3Kγ is involved in hypertension [16,17] by regulating vascular function [17] and particularly myogenic tone, defined as the physiological behavior of resistance arteries to counteract perfusion pressure increases and mainly relying on the constrictor tone of VSMCs [17,36,37,38].…”

Section: Pi3kγ: a Focus On Their Signaling Pathway In Cardiovasculmentioning

confidence: 99%

“…In this regard, it has been shown that PI3Kγ is involved in hypertension [16,17] by regulating vascular function [17] and particularly myogenic tone, defined as the physiological behavior of resistance arteries to counteract perfusion pressure increases and mainly relying on the constrictor tone of VSMCs [17,36,37,38]. Both in experimental animal models of hypertension and in hypertensive patients, it was reported that the increase in peripheral vascular resistances unquestionably contributes to the maintenance of chronic hypertensive status [37,38,39,40,41].…”

Section: Pi3kγ: a Focus On Their Signaling Pathway In Cardiovasculmentioning

confidence: 99%

“…To date, research on the mechanisms underlying hypertension has been focused on the involvement of LTCC in VSMCs dysfunction, providing a molecular target to fight the disease [15,16]. It was initially found that PI3Kγ modulates LTCC functions and expression on plasma membranes of VSMCs through Akt signaling [15,16].…”

Section: Pi3kγ: a Focus On Their Signaling Pathway In Cardiovasculmentioning

confidence: 99%

“…It was initially found that PI3Kγ modulates LTCC functions and expression on plasma membranes of VSMCs through Akt signaling [15,16]. Moreover, PI3Kγ signaling has been shown to be necessary in the activation of Ca 2+ influx in vascular myocytes after stimulation with angiotensin II [47,48].…”

Section: Pi3kγ: a Focus On Their Signaling Pathway In Cardiovasculmentioning

confidence: 99%

See 2 more Smart Citations

The Multifaceted Roles of PI3Kγ in Hypertension, Vascular Biology, and Inflammation

Perrotta

Lembo

Carnevale

2016

IJMS

Self Cite

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PI3Kγ is a multifaceted protein, crucially involved in cardiovascular and immune systems. Several studies described the biological and physiological functions of this enzyme in the regulation of cardiovascular system, while others stressed its role in the modulation of immunity. Although PI3Kγ has been historically investigated for its role in leukocytes, the last decade of research also dedicated efforts to explore its functions in the cardiovascular system. In this review, we report an overview recapitulating how PI3Kγ signaling participates in the regulation of vascular functions involved in blood pressure regulation. Moreover, we also summarize the main functions of PI3Kγ in immune responses that could be potentially important in the interaction with the cardiovascular system. Considering that vascular and immune mechanisms are increasingly emerging as intertwining players in hypertension, PI3Kγ could be an intriguing pathway acting on both sides. The availability of specific inhibitors introduces a perspective of further translational research and clinical approaches that could be exploited in hypertension.

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Identification of PIK3CG as a hub in septic myocardial injury using network pharmacology and weighted gene co‐expression network analysis

Liu

Dong

Escames

et al. 2022

Bioengineering & Transla Med

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Sepsis causes multiple organ injuries, among which the heart is one most severely damaged organ. Melatonin (MEL) alleviates septic myocardial injury, although a systematic and comprehensive approach is still lacking to understand the precise protective machinery of MEL. This study aimed to examine the underlying mechanisms of MEL on improvement of septic myocardial injury at a systematic level. This study integrated three analytic modalities including database investigations, RNA‐seq analysis, and weighted gene co‐expression network analysis (WCGNA), in order to acquire a set of genes associated with the pathogenesis of sepsis. The Drugbank database was employed to predict genes that may serve as pharmacological targets for MEL‐elicited benefits, if any. A pharmacological protein–protein interaction network was subsequently constructed, and 66 hub genes were captured which were enriched in a variety of immune response pathways. Notably, PIK3CG, one of the hub genes, displayed high topological characteristic values, strongly suggesting its promise as a novel target for MEL‐evoked treatment of septic myocardial injury. Importantly, molecular docking simulation experiments as well as in vitro and in vivo studies supported an essential role for PIK3CG in MEL‐elicited effect on septic myocardial injury. This study systematically clarified the mechanisms of MEL intervention in septic myocardial injury involved multiple targets and multiple pathways. Moreover, PIK3CG‐governed signaling cascade plays an important role in the etiology of sepsis and septic myocardial injury. Findings from our study provide valuable information on novel intervention targets for the management of septic myocardial injury. More importantly, this study has indicated the utility of combining a series of techniques for disease target discovery and exploration of possible drug targets, which should shed some light on elucidation of experimental and clinical drug action mechanisms systematically.

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PI3Kγ inhibition reduces blood pressure by a vasorelaxant Akt/L-type calcium channel mechanism

Abstract: Overall our findings suggest that PI3Kγ inhibition could be a novel tool to modulate calcium influx in vascular smooth muscle cells, thus relaxing resistance arteries and lowering blood pressure.

Cited by 45 publications

References 25 publications

Renal Autoregulation in Health and Disease

Renal Autoregulation in Health and Disease

The Multifaceted Roles of PI3Kγ in Hypertension, Vascular Biology, and Inflammation

Identification of PIK3CG as a hub in septic myocardial injury using network pharmacology and weighted gene co‐expression network analysis

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