Abstract
Phosphoinositides, which are membrane-bound phospholipids, are critical signaling molecules located at the interface between the extracellular matrix, cell membrane, and cytoskeleton. Phosphoinositides are essential regulators of many biological and cellular processes, including but not limited to cell migration, proliferation, survival, and differentiation, as well as cytoskeletal rearrangements and actin dynamics. Over the years, a multitude of studies have uniquely implicated phosphoinositide signaling as being crucial in cardiovascular biology and a dominant force in the development of cardiovascular disease and its progression. Independently, the cellular transduction of mechanical forces or mechanotransduction in cardiovascular cells is widely accepted to be critical to their homeostasis and can drive aberrant cellular phenotypes and resultant cardiovascular disease. Given the versatility and diversity of phosphoinositide signaling in the cardiovascular system and the dominant regulation of cardiovascular cell functions by mechanotransduction, the molecular mechanistic overlap and extent to which these two major signaling modalities converge in cardiovascular cells remain unclear. In this review, we discuss and synthesize recent findings that rightfully connect phosphoinositide signaling to cellular mechanotransduction in the context of cardiovascular biology and disease, and we specifically focus on phosphatidylinositol-4,5-phosphate, phosphatidylinositol-4-phosphate 5-kinase, phosphatidylinositol-3,4,5-phosphate, and phosphatidylinositol 3-kinase. Throughout the review, we discuss how specific phosphoinositide subspecies have been shown to mediate biomechanically sensitive cytoskeletal remodeling in cardiovascular cells. Additionally, we discuss the direct interaction of phosphoinositides with mechanically sensitive membrane-bound ion channels in response to mechanical stimuli. Furthermore, we explore the role of phosphoinositide subspecies in association with critical downstream effectors of mechanical signaling in cardiovascular biology and disease.
Highlights
Phosphoinositides (PPIs) constitute less than five percent of all cell membrane phospholipids (Hammond and Hong, 2018) but are essential to the integrity of all living cells (Dickson and Hille, 2019)
PPIs modulate a tremendous breadth of horizontal and vertical cell signaling crosstalk spanning the cell membrane and cytoplasm, respectively, in which high-affinity interactions occur among various pleckstrin homology (PH) domaincontaining membrane-based and cytosolic effector proteins, including protein kinase B (PKB)/Akt, protein kinase C (PKC), phosphoinositide phospholipase C (PLC), 3-phosphoinositidedependent protein kinase-1 (PDK1), and small G proteins (Prestwich, 2004; Ghigo and Li, 2015; Manna and Jain, 2015; De Craene et al, 2017)
The results showed that interactions between PIP2 and the β-tentacle of capping protein Z (CapZ) after molecular stimulation become considerably modified by phosphorylation
Summary
Phosphoinositides (PPIs) constitute less than five percent of all cell membrane phospholipids (Hammond and Hong, 2018) but are essential to the integrity of all living cells (Dickson and Hille, 2019). These findings indicate that members of the Rho GTPase family, RhoA, Rac, and Cdc, are vital in mediating PIP5K activation and, PIP2 synthesis, regardless of their interconversional crosstalk (Oude Weernink et al, 2000; Chatah and Abrams, 2001; Weernink et al, 2004) These GTPases act as a dynamic molecular switch between various cells, which play a key role in vascular pathology (Cai et al, 2015; Karoor et al, 2018; Barlow and Cleaver, 2019) and are involved in mechanosensing and mechanotransduction pathways (Verma et al, 2011; Chaterji et al, 2014; Zegers and Friedl, 2014; Ohashi et al, 2017). A more direct relationship between PI3Kγ and cardiac mechanotransduction
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