Abstract
Mild hyperhomocysteinemia (HHcy, clinically defined as less than 30 μmol/L) is an independent cardiovascular disease (CVD) risk factor, and is associated with many complications during pregnancy, such as preeclampsia (PE). The aim of this study was to assess the effect of long-term mild HHcy on cardiac metabolic function of multiparous rats. Female rats were mated 3 to 4 times and were fed with methionine in drinking water to increase plasma Hcy (2.9 ± 0.3 to 10.5 ± 2.3 μmol/L) until termination. This caused significant increase of heart weight/body weight (0.24 ± 0.01 to 0.27 ± 0.01 g/100 g) and left ventricle weight (0.69 ± 0.03 to 0.78 ± 0.01 g). Superoxide production was increased by 2.5-fold in HHcy hearts using lucigenin chemiluminescence. The ability of bradykinin and carbachol to regulate myocardial oxygen consumption (MVO2) in vitro was impaired by 59% and 66% in HHcy heart, and it was restored by ascorbic acid (AA), tempol, or apocynin (Apo). Protein expression of p22phox subunit of NAD(P)H oxidase was increased by 2.6-fold, but there were no changes in other NAD(P)H oxidase subunits, NOSs or SODs. Microarray revealed 1518 genes to be differentially regulated (P < 0.05). The mRNA level of NAD(P)H oxidase subunits, NOSs or SODs remained unchanged. In conclusion, long-term mild HHcy increases cardiac superoxide mainly through regulation of p22phox component of the NAD(P)H oxidase and impairs the ability of NO to regulate MVO2 in heart of multiparous mothers.
Highlights
Hyperhomocysteinemia (HHcy) is common in women, and can be induced for genetic or nutritional reasons, such as deficiency in cystathionine-b-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR), vitamin, or folic acid (Perry 1999)
total peripheral resistance (TPR) was more than 30% higher in HHcy rats compared to control, suggesting an impairment of peripheral endothelial function
The major findings of this study include: (1) mild HHcy caused hypertension in multiparous rats; (2) NAD(P)H oxidase-derived superoxide production was significantly increased without an apparent increase in antioxidants and antioxidant enzymes; (3) increased superoxide attenuated the ability of BK or Cch to regulate MVO2 in vitro, and this effect was restored by antioxidant treatment; and (4) cardiac gene expression profile differed between HHcy and control groups
Summary
Hyperhomocysteinemia (HHcy) is common in women, and can be induced for genetic or nutritional reasons, such as deficiency in cystathionine-b-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR), vitamin, or folic acid (Perry 1999). Mild HHcy, defined clinically as less than 30 lmol/L, has been recognized as an independent risk factor for a variety of cardiovascular diseases (CVD) including coronary artery disease, peripheral arterial disease and chronic heart failure (Perry 1999; Zylberstein et al 2004; Vizzardi et al 2009). Women with a history of these complications are at higher risk to repeat in subsequent pregnancies and higher risk of CVD in later life (Varvarigou 2010; Duckitt and Harrington 2005; Bellamy et al 2007). Given the well documented correlation between mild HHcy (~ 10 lmol/ L) and CVD, we hypothesize that mild HHcy contributes to the cardiac dysfunction in pregnancy-related complications such as PE, and may account for the increased risk of reoccurrence and CVD in later life.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
