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Background
Cardiovascular disease (CVD) especially acute coronary syndrome (ACS) is a major global cause of death [1]. The most serious of which is the ST-segment elevation myocardial infarction (STEMI) [2].
Primary percutaneous coronary intervention (PPCI) is the recommended and most effective treatment for STEMI, in terms of restoring blood flow and reducing the incidence of recurrent ischemia/infarction. However, in a significant proportion of patients, revascularization does not improve myocardial perfusion because suboptimal coronary reperfusion can occur. Coronary flow can be slow, incomplete, or absent in the affected coronary artery despite evidenced revascularization. This is referred to as no-reflow (NR) or microvascular obstruction (MVO) [3].
The reperfusion process can adversely affect the cardiac muscle and, paradoxically, contribute to additional ischemia, referred to as myocardial ischemia–reperfusion injury (IRI). Its presence in post-PPCI is a poor prognostic factor linked with the occurrence of major adverse cardiac events (MACEs), reduced left ventricular ejection fraction (LVEF), and adverse remodeling of the left ventricle [4].
Ischemia–reperfusion injury is supposed to occur due to the sudden release of reactive oxygen species (ROS). Toxic accumulation of ROS combined with the disparity between pro-inflammatory and anti-inflammatory responses, generates rapid and severe damage to protein, lipid, nucleic acid, and other macromolecules, which can ultimately lead to acute, irreversible myocardial cell death [5].
Accordingly, pharmacological interventions targeting mitochondrial dysfunction, oxidative stress, and inflammation are being extensively evaluated as potential cardioprotective interventions against myocardial IRI. However, while preclinical studies showed promising results with these agents, the findings from human clinical studies have been mixed and inconclusive [6].
Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme, essential for detoxifying reactive aldehydes in various body tissues, a process through which ALDH2 protects the myocardium during ischemia–reperfusion, since reactive aldehydes formed under oxidative stress harm proteins and damage cells [7].
Clinical studies involving the activation of ALDH2 have shown that improved detoxification of reactive aldehydes, such as 4-hydroxynonenal (4-HN), is protective against various cardiovascular morbidities [8, 9, 10–11]. Moreover, an ALDH2 activator, termed (Alda-1), was shown to have therapeutic potential in peripheral arterial disease [12], IRI [13], and angina with glyceryl trinitrate (GTN) tolerance [14].
Also, Paraoxonase-1 (PON-1) exerts a major role in maintaining the antioxidant and anti-inflammatory activities of high-density lipoprotein (HDL) cholesterol, which confers major cardioprotective effects. PON-1...