Chronic, low-dose TMAO treatment reduces diastolic dysfunction and heart fibrosis in hypertensive rats

Abstract

Several studies have suggested negative effects of trimethylamine oxide (TMAO) on the circulatory system. However, a number of studies have shown protective functions of TMAO, a piezolyte and osmolyte, in animals exposed to high hydrostatic and/or osmotic stress. We evaluated the effects of TMAO treatment on the development of hypertension and its complications in male spontaneously hypertensive rats (SHRs) maintained on water (SHR-Water) and SHRs drinking TMAO water solution from weaning (SHR-TMAO). Wistar-Kyoto (WKY) rats were used as normotensive controls to discriminate between age-dependent and hypertension-dependent changes. Telemetry measurements of blood pressure were performed in rats between the 7th and 16th weeks of life. Anesthetized rats underwent echocardiographic, electrocardiographic, and direct left ventricular end-diastolic pressure (LVEDP) measurements. Hematoxylin and eosin as well as van Gieson staining for histopathological evaluation were performed. Plasma TMAO measured by chromatography coupled with mass spectrometry was significantly higher in the SHR-Water group compared with the WKY group (~20%). TMAO treatment increased plasma TMAO by four- to fivefold and did not affect the development of hypertension in SHRs. Sixteen-week-old rats in the SHR-Water and SHR-TMAO groups (12-wk TMAO treatment) showed similar blood pressures, angiopathy, and cardiac hypertrophy. However, the SHR-TMAO group had lower plasma NH2-terminal pro-B-type natriuretic peptide, LVEDP, and cardiac fibrosis. In contrast to age-matched WKY rats, 60-wk-old SHRs showed hypertensive angiopathy and heart failure with preserved ejection fraction. Compared with the SHR-Water group, the SHR-TMAO group (56-wk TMAO treatment) showed significantly lower plasma NH2-terminal pro-B-type natriuretic peptide and vasopressin, significantly lower LVEDP, and cardiac fibrosis. In conclusion, a four- to fivefold increase in plasma TMAO does not exert negative effects on the circulatory system. In contrast, increased dietary TMAO seems to reduce diastolic dysfunction in pressure-overloaded hearts in rats. NEW & NOTEWORTHY Chronic, low-dose trimethylamine oxide (TMAO) treatment that increases plasma TMAO by four- to fivefold reduces plasma NH2-terminal pro-B-type natriuretic peptide and vasopressin, left ventricular end-diastolic pressure, and cardiac fibrosis in pressure-overloaded hearts in hypertensive rats. Our study provides evidence that a moderate increase in plasma TMAO does not have a negative effect on the circulatory system. In contrast, increased dietary TMAO seems to reduce diastolic dysfunction in the pressure-overloaded heart.

Urinary TMAO Levels Are Associated with the Taxonomic Composition of the Gut Microbiota and with the Choline TMA-Lyase Gene (cutC) Harbored by Enterobacteriaceae

“…In particular, TMAO was proposed to promote atherogenesis by increasing cholesterol in macrophages and enhancing the accumulation of foam cells in artery walls [4,5]. Nonetheless, the literature has contradicted the role of TMAO, and recent studies have questioned its deleterious role in the cardiovascular system [6], suggesting, on the contrary, that TMAO could have protective functions [7,8].…”

A Pilot Study on the Effects of l-Carnitine and Trimethylamine-N-Oxide on Platelet Mitochondrial DNA Methylation and CVD Biomarkers in Aged Women

“…On the contrary, the increase in D-loop methylation was associated with improved lipid profile in studied subjects. It is important to mention that a moderate TMAO increase has been previously demonstrated to be able to induce positive effects on the cardiovascular system [53,73]. Moreover, it has been hypothesized that the association of TMAO and CVD might be actually due to the abundance of TMA-producing bacteria in the gut, rather than to the direct effect of circulating TMAO (which could be indirectly associated and likely to be the result of dysbiotic gut microbiota) [74].…”

TMAO, a seafood-derived molecule, produces diuresis and reduces mortality in heart failure rats

“…by the liver to TMAO, therefore the increased plasma TMAO is simply a proxy of the plasma level of toxic TMA. What is more, recent experimental studies provide evidence for beneficial action of TMAO at low doses [2,4,7].…”

“…The jugular vein was cannulated for fluid infusions, and the carotid artery for ABP measurement with Biopac MP 150 (Biopac Systems, USA). The bladder was exposed from an abdominal incision and was cannulated for timed urine 7 collection. After the end of surgery, 20-30 min was allowed for stabilization.…”

“…However, other studies have not confirmed this relationship [14,24,34]. Furthermore, there are contradictory experimental data regarding the effect of TMAO on the circulatory system [2,4,7,16,21].…”