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

Abstract

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.

Function, Regulation and Biological Roles of PI3Kγ Variants

“…Macrophages act in concert with neutrophils at the front line of innate immunity, and interact with components of the acquired immune system. PI3Kγ was found to be involved in various steps of macrophage activation and function [39,114,129]. This includes FcRγ signaling, chemotaxis, release of ROS, secretion of inflammatory mediators, and phagocytosis of pathogens [130,131,132,133,134].…”

Characterization of coordinated growth in macrodactyly caused by somatic mosaic activating mutations inPIK3CA

“…PIK3CG encodes a subunit of PIK3γ kinase. While PI3Kα and PI3Kβ are broadly expressed, PIK3γ is predominantly active in immune cells, vascular smooth muscle and cardiac cells (Perrotta et al, 2016). The S442Y mutation is predicted to be deleterious (Polyphen-2 0.984; SIFT) suggesting function of this change.…”

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

“…142 Furthermore, PI3K isoforms may help regulate blood pressure via type-1 angiotensin-receptor signaling which has led to exploration of the therapeutic antihypertensive utility of this pathway. 134 PI3K pathway may also play a significant role in pathologic remodeling, hypertrophy, and contractility in the heart which should encourage a degree of caution for cardiovascular toxicities particularly amongst the elderly whilst taking these medications. 143 Interestingly, disruption of this cascade pathway via PI3K isoform inhibition has been investigated both in vivo and in various animal models with promising results in the prevention and progression of pulmonary hypertension.…”

“…132 Hypertensive effects of copanlisib appear to be rapid in onset, within 2 hours of starting treatment, and do not appear to be lasting; however, the mechanism of this transient effect is unknown. 134 Copanlisib combinations with MEK inhibitor refamentinib 135 or HER2 (human epidermal growth factor receptor 2) inhibitor trastuzumab 136 have been associated with an even higher incidence of grade 3+ hypertension of 26% and 33%, respectively. Hypertension does not appear to be class effect of all PI3Ki.…”