Heme in Cardiovascular Diseases: A Ubiquitous Dangerous Molecule Worthy of Vigilance

Abstract

Heme, the protoporphyrin IX iron complex is widely present in the human body and it is involved in oxygen storage, electron transfer, and enzymatic reactions. However, free heme can be toxic as it catalyzes the production of reactive oxygen species, oxidizes lipids and proteins, and causes DNA damage, thereby inducing a pro-inflammatory environment. The generation, metabolism, and degradation of heme in the human body are regulated by precise mechanisms to ensure that heme remains non-toxic. However, in several types of cardiovascular diseases, impaired metabolism and exposure to heme may occur in pathological processes, including neovascularization, internal hemorrhage, ischemia, and reperfusion. Based on years of research, in this review, we aimed to summarize the underlying mechanisms by which heme contributes to the development of cardiovascular diseases through oxidative stress, relative pathway gene expression regulation and phenotypic changes in cells. Excess heme plays a detrimental role in atherosclerosis, heart failure, myocardial ischemia-reperfusion injury, degenerative aortic valve stenosis, cardiac iron overload. Recent researches revealed that in some cases heme involved in cardiac damage though ferroptosis. Thus, heme concentrations beyond normal levels are dangerous. Further research on the role of heme in cardiovascular diseases is needed.

Oxidative stress, inflammation, dysfunctional redox homeostasis and autophagy cause age-associated diseases

“…There have been extensive studies on the effects of the upregulation of Nrf2-HO-1 which could alleviate and prevent AADs, particularly inflammatory and autoimmune diseases, including multiple sclerosis (MS), IBDs, systemic lupus erythematosus (SLE), and rhumatoid athritis [32]. Additionally, several AADs and related diseases have also been reported to be alleviated by the upregulation of Nrf2-HO-1, for example, obesity, NAFLD, related metabolic syndromes including hypertension, arthrosclerosis, and CVD [128][129][130][131][132]. Nrf2 activation counteracts OS, inhibits inflammation, and promote AP; thus, the Nrf2-HO-1 system is critical for preventing the onset of DM and its entailed vascular, cardiac, and kidney complications [133][134][135][136].…”

Applications of the Whole-Cell System in the Efficient Biosynthesis of Heme

“…By causing irreversible damage to nucleic acids, proteins, and oxidized membranes, these reactive oxygen species create a pro-inflammatory environment detrimental to cell growth and heme production. Therefore it is necessary to monitor intracellular hemoglobin in real time [78,80].…”

Heme Interactions as Regulators of the Alternative Pathway Complement Responses and Implications for Heme-Associated Pathologies

“…• Severe hematological disorders such as acute intermittent porphyrias [61] and anemias [5] that include congenital sideroblastic anemia [62] and Diamond-Blackfan anemia [63,64] • Inflammation [48,49,65] • Hemolytic syndromes [66] • Severe sepsis [65] • Stroke [38,39,[56][57][58] • Neurodegeneration [67,68] • Neurological disorders [69,70] • Cardiovascular arrythmias [71,72] Heme-Associated Complementopathies [73] • Hemostasis-driven thromboinflammation [74] • Paroxysmal nocturnal hemoglobinuria (PNH) [75,76] • Hemolytic diseases and cell lysis conditions such as hemolytic uremic syndromes, hemorrhage, sepsis and sickle cell disease [53,77,78] • Age-related macular degeneration (AMD) [75,79,80] • Ferroptosis in traumatic brain injury [68] • Ischemic stroke with cerebral hemorrhage [81] • Neurodegeneration [82] • Huntington's disease [83] 1.…”