Discovery and therapeutic implications of bioactive dihydroxylated phenolic acids in patients with severe heart disease and conditions associated with inflammation and hypoxia

Abstract

Our initial studies detected elevated levels of 3,4-dihydroxyphenyllactic acid (DHPLA) in urine samples of patients with severe cardiac symptoms when compared with healthy subjects. In view of the reported anti-inflammatory properties of DHPLA and related dihydroxylated phenolic acids (DPAs), we embarked on a multi-centre investigation to establish the possible pathophysiological significance and therapeutic implications of these findings. Chinese and Caucasian patients with severe cardiac symptoms and those being treated for conditions associated with inflammation (WBC ≥ 10×10⁹/L or hsCRP ≥ 3.0 mg/L) and/or hypoxia (PaO₂ ≤ 75 mmHg) were enrolled, their urine samples were analyzed by HPLC, HPLC-MS, GC-MS and biotransformation assays. DHPLA was detected in urine samples of patients, but undetectable in healthy volunteers. Dynamic monitoring of inpatients undergoing treatment showed their DHPLA levels declined in proportion to their clinical improvement. Proteus vulgaris and P. mirabilis were significantly more abundant in DHPLA-positive patients’ fecal samples than healthy volunteers. In culture, these bacteria were capable of reversible interconversion between DOPA and DHPLA. Furthermore, porcine and rodent organs were able to metabolize DOPA to DHPLA and related phenolic acids. The elevated levels of DHPLA in these patients suggest anti-inflammatory DPAs are generated de novo as part of a human’s defense mechanism against disease. Given that DHPLA isolated from Radix Salvia miltiorrhizae has multi-dimensional pharmacological activities, these data demonstrate not only scientific basis of the ethnopharmacological uses of this medicinal plant but also highlight the therapeutic potential of endogenous, natural or synthetic DPAs and their derivatives in humans.

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