Molecular mechanisms underlying some major common risk factors of stroke

Abstract

Ischemic and hemorrhagic strokes are the most common known cerebrovascular disease which can be induced by modifiable and non-modifiable risk factors. Age and race are the most common non-modifiable risk factors of stroke. However, hypertension, diabetes, obesity, dyslipidemia, physical inactivity, and cardiovascular disorders are major modifiable risk factors. Understanding the molecular mechanism mediating each of these risk factors is expected to contribute significantly to reducing the risk of stroke, preventing neural damage, enhancing rehabilitation, and designing suitable treatments. Abnormalities in the structure of the blood-brain barrier and blood vessels, thrombosis, vasoconstriction, atherosclerosis, reduced cerebral blood flow, neural oxidative stress, inflammation, and apoptosis, impaired synaptic transmission, excitotoxicity, altered expression/activities of many channels and signaling proteins are the most knows mechanisms responsible for stroke induction. However, the molecular role of risk factors in each of these mechanisms is not well understood and requires a lot of search and reading. This review was designed to provide the reader with a single source of information that discusses the current update of the prevalence, pathophysiology, and all possible molecular mechanisms underlying some major risk factors of stroke namely, hypertension, diabetes mellitus, dyslipidemia, and lipid fraction, and physical inactivity. This provides a full resource for understanding the molecular effect of each of these risk factors in stroke.

Keywords: Mechanism; Molecular; Pathways; Risk factors; Stroke.

Figure 1

Modifiable, non-modifiable risk factors and triggers of ischemic and hemorrhagic strokes.

Figure 2

Molecular mechanisms by which hypertension increases the risk of stroke through modifying the structure and function of the cerebral blood vessels. Diverse mechanisms include increasing smooth muscle hypertrophy, inward remodeling, promoting endothelial dysfunction, atherosclerosis, vasoconstriction, thrombosis, and vessel stiffness, and reducing cerebral blood flow (CBF). Increasing intraluminal pressures stimulates muscle contraction and vasoconstriction by activating phospholipase C (PLC) and subsequent production of inositol triphosphate (IP3) and intracellular Ca²⁺ which induces vessel vasoconstriction. However, ANG II generates large quantities of reactive oxygen species (ROS) through activating NADPH oxidase. In turn, ROS induces vessel structural changes, apoptosis, inflammation, and vasoconstriction by activating the caveolin-1 (Cav-1)/PI3K/Akt axis, stimulating NF-κB and the expression of diverse adhesive and inflammatory cytokines, inducing vasoconstriction through the further generation of scavenging nitric oxide (NO) and peroxynitrite oxidants (ONOO-), upregulating endothelin-1 (ET-1), and activating poly-ADP-ribose polymerase (PARP), upregulating the matrix metalloprotease-9 (MMP-9), scavenging antioxidants like manganese superoxide dismutase (MnSOD) and glutathione (GSH); increasing the oxidation of low-density lipoprotein cholesterol (ox-LDL) which promotes atherosclerosis; downregulating and inhibiting of small- and intermediate-conductance calcium-activated potassium (SK_Ca/IK_Ca) and potassium (Kir_2.x) channels; and inducing endoplasmic reticulum (ER) stress. EGFR: epidermal growth factor receptor, IL-6: interleukin-6; ICAM: intracellular cell adhesion molecule, VCAM: vascular cell adhesion molecule, AT-1: angiotensin receptor type 1.

Figure 3

Molecular mechanisms by which type 1 and type 2 diabetes mellitus (DM) (T1DM and T2DM) increase the risk of ischemic and hemorrhagic strokes. In the figure, T2DM is mainly associated with insulin resistance (IR) and hyperinsulinemia which increases blood pressure (BP) through stimulating sodium (Na⁺) resorption and promoting dyslipidemia and atherosclerosis. On the other hand, T1DM1 increases the risk of arrhythmias, atrial fibrillation (AF), myocardial infarction (MI), heart failure (HF), and other cardiovascular disorders (CVDs) by hypoinsulinemia-induced impairment in the function of Na+/K + ATPase and promoting hyperkalemia. However, hyperglycemia-induced by both types of DM can increase blood pressure by inducing hyperosmolarity and activating the sympathetic nervous system (SNS). In addition, hyperglycemia can promote cardiovascular disorders such as diabetic cardiomyopathy (DC) and atherosclerosis and raises blood pressure by promoting inflammation and oxidative stress and through overproduction of reactive oxygen species (ROS), activating NF-κB, and scavenging nitric oxide (NO). Mechanisms behind the effects afforded by hyperglycemia include activating numerous damaging pathways such as NADPH oxidase, hexosamine, polyol; protein kinase C (PKC), and advanced glycation products.

Figure 4

Molecular mechanisms by which hyperlipidemia increases the risk of stroke. Ischemic stroke risk is increased with triglycerides (TGs), low-density lipoprotein cholesterol (LDL-c), and total cholesterol levels higher than 500, 160, and 240 mg/dl, respectively. Also, LDL-c/HDL-c > 35 or TC/HDL ratio >35 and 6, respectively increase the risk of ischemic stroke. inflammation and increased production of reactive oxygen species (ROS) are the major underlying mechanisms leading to ischemic stroke. The mechanism by which hyperlipidemia induces oxidative stress and inflammation is shown in the left lower panel of the figure. On the other hand, the major pathways involved in hyperlipidemia-induced ischemic and hemorrhagic strokes include promoting thrombosis and atherosclerosis, and neural damage and apoptosis, reducing cerebral blood flow, increasing blood-brain barrier (BBB) permeability, and promoting obesity, hypertension, cardiovascular disorders (CVDs) and insulin resistance IR. The underlying mechanisms of all these pathways are shown in the figure.

Figure 5

Molecular mechanisms mediating the neuroprotective effect of exercise in preventing stroke and improving post-stroke outcome. Accordingly, major effects of exercise are shown on the left panel. However, exercise can stimulate neural synaptic plasticity, excitability, and neurogenesis by stimulating the expression of BDNF, vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF-1). BDNF seems to be a key signaling molecule that further stimulates the synaptic protein expression by stimulating the CREB/synaptic protein axis. In addition, BDNF stimulates neural energy metabolism and suppresses oxidative stress, inflammation, and apoptosis by increasing the activation of AMPK. In addition, exercise stimulates cell survival and inhibits cell apoptosis by activating the PI3K/Akt survival axis, as well as upregulating antioxidants, heat shock proteins (HSPs), and the anti-apoptotic protein (Bcl2). Also, exercise preserve the integrity of the blood-brain barrier (BBB) by suppressing the activation of the myeloperoxidase-9 (MPP-9). Furthermore, exercise increases cerebral blood flow (CBF) by downregulating endothelin-1 (ET-1) and increasing the expression of netrin-1 and its receptors, the uncoordinated gene 5B (Unc5B), and the deleted in colorectal cancer (DCC). Lastly, exercise prevents neural excitotoxicity by downregulating the metabotropic glutamate receptor 5 (mGluR5) and N-methyl-D-aspartate receptor subunit type 2B (NR2B).