Luteolin: A Flavonoid that Has Multiple Cardio-Protective Effects and Its Molecular Mechanisms

Abstract

Cardiovascular disease (CVD) has become the leading cause of morbidity and mortality worldwide. A well-monitored diet with a sufficient intake of fruits and vegetables has been confirmed as a primary prevention of CVD. Plant constituents such as flavonoids have been shown to confer healthy benefits. Luteolin (Lut), a kind of flavonoid, possesses anti-oxidative, anti-tumor, and anti-inflammatory properties. Recent scientific literature has reported the cardiac protective effects of Lut in vitro and in vivo. Therefore, the aim of this review is to provide an update and detailed overview with cardio-protective molecular mechanisms of Lut with a focus on multiple intrinsic and extrinsic effectors. We further explore how these mechanisms participate in ischemia/reperfusion (I/R) injury, heart failure (HF) and atherosclerosis (AS). A proper understanding of the cardiovascular protective effects and the relative mechanisms of Lut may provide the possibility of new drug design and development for CVD. With the previous studies mainly focused on basic research, we need to advance the prospects of its further clinical utilization against CVD, large prospective clinical trials of Lut are needed to observe its therapeutic effects on patients with I/R injury, HF and AS, especially on the effective therapeutic dosage, and safety of long-term administration.

Keywords: I/R injury; atherosclerosis; cardio-protection; heart failure; luteolin; target effectors.

FIGURE 1

The basic structure of Lut consists of an aromatic A-ring and a heterocyclic C-ring, which are connected with an aromatic B-ring through a carbon-carbon bridge.

FIGURE 2

Lut alleviates I/R injury by inhibiting apoptosis by up-regulating AKT, increasing BCL-2 protein and decreasing BAX protein. SERCA2a is the key protein involved in Ca²⁺ uptake from the cytosol into the SR. SERCA2a activity is improved after activation of the PI3K/AKT signaling pathway; at the same time, Lut works as a p38 MAPK pathway inhibitor to suppress the phosphorylation of PLN, thereby enhancing the activity of SERCA2a and reducing the Ca²⁺ overload. Oxidative stress is blocked by Lut through HO-1, which enhances the binding of Nrf2 to the ARE. Lut inhibits JUK and increases p-ERK1/2 to enhance the contraction of cardiomyocytes. Lut up-regulates the myocardial eNOS pathway and inhibits the mitochondrial permeability transition pore to protect the heart against I/R injury.

FIGURE 3

In HF, SERCA2a is a vital target regulated by Lut for effective cardiomyocyte contraction and relaxation. Inhibition of SERCA2a activity markedly abolishes Lut-induced benefits in vitro and in vivo. Autophagy is a self-protection response to stress in HF. Lut up-regulates autophagy through MST1 inhibition, alleviating post-infarction cardiac dysfunction and enhancing autophagic flux in the neonatal cardiomyocytes after hypoxia. Lut protects against cardiac fibrosis and hypertrophy by blocking the Ang II-TGFβ1 signaling pathway, and suppressing expression of TGFβ1.

FIGURE 4

H₂O₂, PDGF, and AngII are stimuli for VSMC proliferation and migration. An inhibitory effect on the Ang II-induced VSMC proliferation and migration rate was observed following pretreatment with Lut. Lut decreases p-AKT (308) and p-AKT (473) expression to inhibit VSMC proliferation and migration. Lut blocks H₂O₂-triggered SRC phosphorylation. ATP-binding pocket may be the Lut-binding site in SRC. Lut affects the TNF-α and IL-6 mRNA stability from inhibiting the p38 and MK2 phosphorylation levels by promoting TTP expression. The mRNA stability is known to impact inflammatory processes by regulating inflammatory gene expression. Lut suppresses TNF-α-activated ROS generation, and decreases the NOX4 and p22^phox expression as well as attenuates oxidative stress through the NOX4/ROS-NF-κB pathways.