Gender differences in GRK2 in cardiovascular diseases and its interactions with estrogen

Abstract

G protein-coupled receptor kinase 2 (GRK2) is a multifunctional protein involved in regulating G protein-coupled receptor (GPCR) and non-GPCR signaling in the body. In the cardiovascular system, increased expression of GRK2 has been implicated in the occurrence and development of several cardiovascular diseases (CVDs). Recent studies have found gender differences in GRK2 in the cardiovascular system under physiological and pathological conditions, where GRK2's expression and activity are increased in males than females. The incidence of CVDs in premenopausal women is lower than in men of the same age, which is related to estrogen levels. Given the shared location of GRK2 and estrogen receptors, estrogen may interact with GRK2 by modulating vital molecules such as calmodulin (CaM), caveolin, RhoA, nitrate oxide (NO) and Mouse double minute 2 homolog (Mdm2), via signaling pathways mediated by estrogen's genomic (ERα and ERβ), and non-genomic (GPER) receptors, conferring cardiovascular protection in females. Highlighting the gender differences in GRK2 and understanding its interaction with estrogen in the cardiovascular system is pertinent in treating gender-related CVDs. As a result, this article explores the gender differences of GRK2 in the cardiovascular system and its relationship with estrogen during disease conditions. Estrogen's protective and therapeutic effects and its mechanism on GRK2-related cardiovascular diseases have also been discussed.

Effectiveness of exercise training on arterial stiffness and blood pressure among postmenopausal women: a systematic review and meta-analysis

“…The incidence of hypertension is significantly higher in postmenopausal women [ 1 , 2 ]. Menopause is one of the risk factors for cardiovascular diseases [ 3 ], with sex hormone deficiency [ 4 ], endothelial dysfunction [ 5 ], and arterial stiffness [ 6 ]. It has been proved that estrogen plays an important role in inducing the mobilization of endothelial progenitor cells in the bone marrow to promote angiogenesis and repair endothelial damage [ 7 ].…”

“…It has been proved that estrogen plays an important role in inducing the mobilization of endothelial progenitor cells in the bone marrow to promote angiogenesis and repair endothelial damage [ 7 ]. However, estrogen deficiency reduces the repair capacity of endothelial cells, ultimately leading to arterial damage and endothelial dysfunction in older women [ 4 , 8 , 9 ]. Abnormal blood pressure may result from decreased arterial compliance associated with endothelial dysfunction [ 10 , 11 ].…”

Estradiol mitigates stress-induced cardiac injury and inflammation by downregulating ADAM17 via the GPER-1/PI3K signaling pathway

“…E2 is the most active form of estrogen, mainly produced by the ovaries, and plays a key role in the female reproductive system, as well as other physiological processes via the activation of its receptors, including G protein-coupled estrogen receptor 1(GPER-1), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) [ 5 ]. ERα and ERβ are mainly genomic receptors that can exert their functions by binding to estrogen response elements in the promoter region of target genes or transcription factor complexes [ 6 ]. Also, compared to ERα and ERβ, GPER-1 is more abundant, acts more rapidly, and mostly exerts its function at the membrane and cytosolic levels [ 6 ].…”

“…ERα and ERβ are mainly genomic receptors that can exert their functions by binding to estrogen response elements in the promoter region of target genes or transcription factor complexes [ 6 ]. Also, compared to ERα and ERβ, GPER-1 is more abundant, acts more rapidly, and mostly exerts its function at the membrane and cytosolic levels [ 6 ]. Increasing evidence reveals that E2 is cardioprotective through various mechanisms mediated by its receptors during stress [ 7 , 8 ].…”