Biogenic Aldehydes as Therapeutic Targets for Cardiovascular Disease

Abstract

Aldehydes are continuously formed in biological systems through enzyme-dependent and spontaneous oxidation of lipids, glucose, and primary amines. These highly reactive, biogenic electrophiles can become toxic via covalent modification of proteins, lipids and DNA. Thus, agents that scavenge aldehydes through conjugation have therapeutic value for a number of major cardiovascular diseases. Several commonly-prescribed drugs (e.g., hydralazine) have been shown to have potent aldehyde-conjugating properties which may contribute to their beneficial effects. Herein, we briefly describe the major sources and toxicities of biogenic aldehydes in cardiovascular system, and provide an overview of drugs that are known to have aldehyde-conjugating effects. Some compounds of phytochemical origin, and histidyl-dipeptides with emerging therapeutic value in this area are also discussed.

Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation

“…One alternative to antioxidant suppression of LDE production involves using carbonyl-trapping molecules to directly intercept reactive LDEs within cells and tissues [16][17][18][19]. Since LDEs are less likely to play the essential cell signalling functions attributed to reactive oxygen species, this strategy seems less susceptible to the side-effects that hamper clinical translation of radicalquenching antioxidants.…”

“…Newer theories tend to attribute steatosis to transcriptional upregulation of various lipogenic genes driven by such ligand-responsive transcription factors as SREBP, PPAR α and PXR[68,69], or a suppression of the inhibitory effects of AMP-activated protein kinase upon acetyl CoA carboxylase activity, the rate-limiting enzyme in fatty acid synthesis[70].A novel alternative pro-steatotic mechanism emerged with growing knowledge of the role of toxic LDEs in ALD. Several factors increase the vulnerability of hepatocytes to LPO during ethanol exposure, including formation of reactive oxygen species via such routes as CYP2E1-catalysed ethanol oxidation; a shift in the mitochondrial NADH redox state; and the activation of NADPH19 oxidases within macrophages. Since membrane PUFAs are fragmented during this barrage of endogenous oxidants, the hepatic proteome of heavy drinkers readily accumulates damage by multiple LDEs including acrolein and other α,β-unsaturated aldehydes[71].…”

Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action

“…Generation of biogenic aldehydes has a significant effect on neuroinflammation associated with Alzheimer's and cardiovascular disease-associated fibrosis, vascular changes, and cardiac hypertrophy (Pan et al, 2016;Nelson et al, 2017;Joshi et al, 2019). Specifically, MAO-dependent aldehyde generation induced mitochondrial dysfunction and ultimately led to heart failure in a pressure overload animal model (Deshwal et al, 2017).…”

Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α

“…The high reactivity of aldehydes has often been a major issue for developing safe drugs, even in the discovery of Bortezomib (boronic acid proteasome inhibitor, Figure 1). 24,25 In contrast, the lower reactivity of boronic acids and nitriles allowed medicinal chemists to use them as warhead in drugs such as Bortezomib and Vildagliptin (nitrile-containing covalent DPP-IV inhibitor, Figure 1). This potency trend followed this reactivity order, with the aldehyde being the most intrinsically reactive electrophile and thus the most potent inhibitor, confirming that intrinsic reactivity is a factor for optimal enzyme inhibition.…”