The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

Abstract

Diabetic cardiomyopathy is one of the major mortality risk factors among diabetic patients worldwide. It has been established that most of the cardiac structural and functional alterations in the diabetic cardiomyopathy condition resulted from the hyperglycemia-induced persistent oxidative stress in the heart, resulting in the maladaptive responses of inflammation and apoptosis. Flavonoids, the most abundant phytochemical in plants, have been reported to exhibit diverse therapeutic potential in medicine and other biological activities. Flavonoids have been widely studied for their effects in protecting the heart against diabetes-induced cardiomyopathy. The potential of flavonoids in alleviating diabetic cardiomyopathy is mainly related with their remedial actions as anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-apoptotic agents. In this review, we summarize the latest findings of flavonoid treatments on diabetic cardiomyopathy as well as elucidating the mechanisms involved.

Keywords: diastolic dysfunction; flavanol; flavone; flavonol; isoflavone; systolic dysfunction.

Figure 1

Events in the development and progression of diabetic cardiomyopathy (DCM) initiated by diabetes-induced uncontrolled cardiac remodeling. The early stage of DCM mainly characterized by diastolic dysfunction will progress to late stage as systolic dysfunction appears, eventually leading to heart failure.

Figure 2

Summary of the mechanisms involved in the pathogenesis of diabetic cardiomyopathy. Hyperglycemia and hyperlipidemia resulting from insulin dysregulation induces excessive production of reactive oxygen and nitrogen species (ROS and RNS), generating oxidative stress in the cardiomyocytes. ROS also activates protein kinase C (PKC) pathways, which induces inflammation and cell apoptosis via mitogen-activated protein kinase (MAPK) pathways. Uncontrolled cardiomyocyte deaths lead to cardiac remodeling by cardiomyocyte hypertrophy and myocardial fibrosis as adaptive mechanisms to preserve the integrity of the heart. This structural alteration causes the heart to functionally regress as both diastolic and systolic dysfunction developed, conditions which define diabetic cardiomyopathy.

Figure 3

Chemical structures of different classes of flavonols. All flavanols classes share the same chemical bone, comprising two benzene rings (A and B) linked by a heterocyclic ring. Each flavonols are grouped into their classes based on the connection between the B and C rings as well as the hydoxylation and glycosylation patterns of the three main rings.

Figure 4

Potential of flavonoids in ameliorating diabetic cardiomyopathy, derived from their ability to combat diabetes-induced oxidative stress, inflammation, and apoptosis, which all play key roles in the structural and functional alterations in diabetic cardiomyopathy.