Pyridoxamine improves survival and limits cardiac dysfunction after MI

Abstract

Advanced glycation end products (AGEs) play a key role in the progression of heart failure. Whether treatments limiting AGEs formation would prevent adverse left ventricular remodeling after myocardial infarction (MI) remain unknown. We investigated whether pyridoxamine (PM) could limit adverse cardiac outcome in MI. Rats were divided into MI, MI + PM and Sham. Echocardiography and hemodynamic parameters were used to assess cardiac function 8 weeks post-surgery. Total interstitial collagen, collagen I and collagen III were quantified using Sirius Red and polarized light microscopy. PM improved survival following LAD occlusion. Pre-treatment with PM significantly decreased the plasma AGEs levels. MI rats treated with PM displayed reduced left ventricular end-diastolic pressure and tau compared to untreated MI rats. Deformation parameters were also improved with PM. The preserved diastolic function was related to the reduced collagen content, in particular in the highly cross-linked collagen type I, mainly in the peri-infarct region, although not via TGF-β1 pathway. Our data indicate that PM treatment prevents the increase in AGEs levels and reduces collagen levels in a rat model of MI, resulting in an improved cardiac phenotype. As such, therapies targeting formation of AGEs might be beneficial in the prevention and/or treatment of maladaptive remodeling following MI.

High intensity training improves cardiac function in healthy rats

“…Whether an improved diastolic function related to a decreased fibrosis content following exercise training can be completely ruled out remains to be further confirmed as it has been shown that diastolic function ( i.e . EDP) is directly associated with cardiac fibrosis level 40,41 . However, most experiments examining fibrosis and diastolic function have been performed under pathological settings 39,42 .…”

“…Prior to sacrifice, transthoracic echocardiography was performed under 2% isoflurane in all animals with a Vivid I ultrasound machine (GE Vingmed Ultrasound) using a 10 MHz linear array transducer. The protocol used is as described previously 40,41 . Briefly, a standard parasternal long axis image and short axis views at the mid-ventricular level were obtained at a temporal resolution of approximately 200 frames per second.…”

“…Conductance measurements were performed in all animals with the use of an SPR-320 MikroTip high-fidelity pressure transducer (Millar Inc) that was advanced into the left ventricle via the right carotid artery, as described previously 41 . The pressure catheter (2 F) was connected to a quad-bridge amplifier and PowerLab 26 T module (AD Instruments, United Kingdom) was used to transfer the data to LabChart v7.3.7 software (AD Instruments, United Kingdom).…”

Glycolaldehyde-modified proteins cause adverse functional and structural aortic remodeling leading to cardiac pressure overload

“…More specifically, we observed an increase in collagen type I and collagen type III in HMW-AGEs-injected animals, the predominant subtypes of collagen in artery walls 54 . This increase in interstitial collagen deposition and the content of collagen subtypes has also been observed in the hearts of rats with myocardial infaction (MI) 14 . Interestingly, the increase of collagen deposition with MI was reduced after administering the AGEs-formation inhibitor pyridoxamine.…”

“…nephropathy, neuropathy and retinopathy) complications of diabetes 11 , 12 . Despite optimistic results on the use of anti-AGEs therapies such as aminoguanidine, pyridoxamine, and alagebrium in animal models of increased LMW-AGEs 13 , 14 , clinical evidence on their safety and efficacy is currently weak, suggesting the involvement of other AGEs entities 15 . Previous research has mainly focused on mature LMW-AGEs compounds such as pentosidine and carboxymethyllysine (CML) or their precursors such as methylglyoxal, while the contribution of HMW-AGEs to cardiovascular dysfunction is largely unknown.…”