Research Area

Cardiovascular and Signal Transduction


Introduction of cardiovascular and signal transduction

Cardiovascular disease is a symptom manifested by a disorder of the cardiovascular system. The cardiovascular system is a complicated, ordered system in which signal transduction plays a key regulatory role in this system. There are a series of specific receptors and complex intracellular mechanisms in the cells of the heart and blood vessel walls that allow cells to respond appropriately to external stimuli. These include the G protein-coupled receptor signaling pathway, the redox signaling pathway, the growth factor signaling pathway, the calcium signaling pathway, and the adipokines signaling pathway. Studying the signaling mechanisms by which extracellular stimuli alter the function of the heart and vascular wall cells can provide valuable guidance for the cause and progression of pathological conditions caused by disturbances in the signaling system. This facilitates research for new molecular targets for pharmacological interventions and provides new approaches and perspectives for the treatment of cardiovascular diseases.

Cardiovascular and Signal Transduction

Cell Signaling in the Cardiovascular System

  1. G protein-coupled receptor signaling pathway
  2. The guanine nucleotide regulatory protein (G protein) is an important regulatory role in various signal transduction systems in cardiac and vascular wall cells. These signaling systems include adenylate cyclase/cAMP and phospholipase C (PLC) /phosphatidylinositol turnover (PI). They are associated with the regulation of various physiological functions such as platelets, including platelet aggregation, secretion and blood clot formation, and cardiovascular function, including arterial tone and reactivity. In clinical studies, the abnormal change of adenylate cyclase activity, cAMP levels, G protein and PLC/PKC will change the cardiac and vascular function and are accompanied by the inhibitory G protein (Giα-2 and Giα-3) changed while the level of activating G protein (Gsα) did not change. These changes in G protein occur before blood pressure development, suggesting that over expression of Gi protein may be one of the factors leading to the onset of hypertension. In the cardiovascular system, G protein coupled receptors (GPCRs) essentially involve each regulatory event. Thus, signaling through GPCR can modulate the extent of peripheral arterial resistance, renal function, rate and intensity of myocardial contraction, cardiac hypertrophy and so on. GPCRs in normal cardiovascular function include angiotensin II receptors, endothelin-1 receptor, adrenaline and norepinephrine receptors. GPCR agonists promote this interaction of their respective receptors with the G protein. G protein is a heterotrimer containing α, β and γ subunits. The interaction of the receptor with the G protein promotes the exchange of GDP between GTP and Gα subunits, causing subunit dissociation, while free Gα can further drive activation or inhibition of multiple effector molecules. The Gβγ subunit can interact with different effector molecules to affect downstream signaling pathways. Effector molecules that interact with Gβγ include enzymes (eg, adenylate cyclase; phospholipase) and ion channels. Changes in cell function through a variety of mechanisms. These receptors are expressed on cardiomyocytes, vascular smooth muscle cells (VSMC) and endothelial cells, and through them transduce signals to coordinate normal physiological functions of vascular tone, heart rate and contractility. In addition, due to angiotensin II, endothelin-1 and adrenaline promote the growth of cardiomyocytes, stimulate the proliferation of vascular smooth muscle cells (VSMC), and alter endothelial cell function, signaling through its receptor may also lead to pathological hypertrophy, atherosclerosis and hypertension.

  3. Redox signaling pathway
  4. Reactive oxygen species (ROS) cause ischemic heart disease by causing physiological electrical disturbances, cardiac dysfunction and cell death. Cardiac arrhythmias and convulsions are markers of ROS-mediated cell damage during ischemic myocardial reperfusion. Studies have revealed that the use of antioxidants and free radical scavengers can effectively improve arrhythmias and convulsions during reperfusion. Therefore, the redox response signaling pathway is closely linked to cardiovascular disease.

    Thioredoxin is a class of redox-regulating proteins that are essential factors in various oxidative stress-induced diseases. Clinical studies have found that thioredoxin may play a significant role in cardiovascular disease by inducing its own upregulation to reduce stress damage. Previous studies have revealed that Trx-1 inhibits cardiac hypertrophy and heart failure and improves myocardial ischemia-reperfusion injury. In addition, Trx-1 showed significant effects in relieving hypertension and diabetes.

    Activation of the sympathetic nervous system is critical to control the process of excitation-contraction coupling (ECC) in the heart. The activated cardiac β-adrenergic receptor (β-AR) selectively interacts with activating G protein (Gs), which in turn activates adenylate cyclase (AC), and catalyzes cAMP formation. Subsequently, activation of cAMP-dependent protein kinase A (PKA) leads to phosphorylation of regulatory proteins involved in cardiac ECC and energy metabolism. Studies have shown that the altered cardiac response under pathological conditions is closely linked to the function of the β-AR system.

  5. Growth factor signaling pathway
  6. Studies have found that transactivation of growth factor receptors such as EGF-R, PDGF-R and IGF-1R triggers vasoactive peptide signaling. Vasoactive peptides, such as endothelin-1 (ET-1) and angiotensin II (AngII), are considered as involved in the pathogenesis of vascular abnormalities such as hypertension, atherosclerosis, hypertrophy and restenosis.These peptides trigger a biological effect-related G protein-coupled receptor (GPCR) by activating transmembrane receptors. GPCR can further activate mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3-K) and protein kinase B.These pathways play a major role in cardiovascular disease by affecting the regulation of myocardial and vascular endothelial cell hypertrophy, growth, proliferation, migration and survival.

  7. Calcium signaling pathway
  8. Ca2+ signaling pathway regulation is an important signaling pathway regulation in cells, and is associated with a variety of cellular functions including gene transcription, proliferation, and contraction of vascular smooth muscle. The key mediator of Ca2+ signaling is the multifunctional serine/threonine protein kinase and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Among them, CaMKII has a complicated structure and remarkable automatic adjustment characteristics. In vivo studies, the complexity and variability of CaMKII pose significant challenges for research. Therefore, the CaMKII study needs further exploration. In the study of vascular smooth muscle cells cultured in vitro, it was found that dynamic regulation of CaMKII isoenzyme is an important determinant of vascular smooth muscle phenotype and an integral part of fibroproliferative vascular disease.

  9. Adipokines signaling pathway
  10. The principal source of adipokines is fat cells and plays a major role in the hypothalamus by acting on their receptors (called OBR). Although it was considered that adipokines were only derived from adipose tissue, it was now found that adipokines can be produced by various tissues including the cardiovascular system. Adiponectin is part of the potential factors for the onset of cardiovascular disease due to the association of cardiovascular risk with obesity. Studies have found that adipokines producing blood vessels or cardiomyocyte hypertrophy or hyperplasia appear to be associated with MAPK. In addition, adipokines also activate the p38 and RhoA/ROCK pathways, leading to changes in actin dynamics, which further promote activation of p38, leading to cell hypertrophy.

Scientific significance

Cells involved in the regulation of the homeostasis of the cardiovascular system respond to changes in their local environment through activation of extracellular receptors, with GPCRs being the most important. Signal recognition is transduced intracellularly into phosphorylation state protein kinases and protein phosphatases that focus on the regulation of a range of intracellular proteins. Subtle defects in these mechanisms can lead to cardiovascular disease. This study of signal transduction pathways in the cardiovascular system is important because it can provide more drug targets and methods for the treatment of cardiovascular disease by an understanding of cellular synergy to maintain homeostasis and the coordinated response of multiple signaling.

References:

  1. Dzimiri N. Receptor crosstalk. Implications for cardiovascular function, diseaseand therapy. Eur J Biochem. 2002, 269: 4713–30.
  2. Krupnick JG, Benovic JL. The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Ann Rev Pharmacol Toxicol. 1998, 38:289–319.
  3. Ago T, et al. Thioredoxin1 upregulates mitochondrial proteins related to oxidative phosphorylation and TCA cycle in the heart. Antioxid. Redox Signal. 2006, 8:1635–1650.
  4. Quin F, et al. Vitamin C and E attenuate apoptosis, β-adrenergic receptor desensitization, and sarcoplasmic reticular Ca2+ ATPase downregulation after myocardial infarction. Free Radic. Biol. Med. 2006, 40:1827–1842.
  5. Andresen BT, et al. Role of EGFR transactivation in angiotensin II signaling to extracellular regulated kinase in preglomerular smooth muscle cells. Hypertension. 2003, 41:781–786.
  6. Ahima, R. S., Osei, S. Y. Leptin signaling. Physiol. Behav. 2004, 81:223–241.

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