Effects of the HIV-1 Protein Tat on Myocardial Function and Response to Endotoxin

Abstract

HIV-1 infection has been associated with cardiomyopathy in a subset of patients. In order to determine whether HIV-1 alters myocardial function or the myocardial response to stress, transgenic mice that express the HIV-1 protein Tat were used. Heart function was assessed using the isolated working heart preparation. Response to infection was assessed by measuring heart function at various times after endotoxin administration. Since cytokines are implicated in myocardial dysfunction, plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) and myocardial mRNA and protein levels of TNF-alpha and IL-6 were determined. Tat by itself did not cause myocardial dysfunction; however, 4 h after endotoxin, myocardial function was more severely compromised in the Tat mice than in control mice. Plasma TNF-alpha levels were elevated at 2 h and higher in the control group but myocardial levels were similar in the two groups. Plasma IL-6 was increased but myocardial levels were different only at 24 h at which time myocardial function was no longer depressed. Tat expression, by itself, did not impair intrinsic myocardial function but did increase myocardial injury induced by endotoxin. Although cytokines are associated with dysfunction, TNF-alpha and IL-6 were probably not responsible for the exaggerated dysfunction in Tat mice receiving endotoxin.

HIV-1 Tat Upregulates the Receptor for Advanced Glycation End Products and Superoxide Dismutase-2 in the Heart of Transgenic Mice

“…In this work, we demonstrated that Tat exposure did not significantly alter diastolic or systolic function in Tat-transgenic mice at a young adult age. Our data are consistent with prior preclinical findings using Tat-exposed young mice that reported no functional change in heart physiology [ 84 , 85 ]. However, LV dysfunction was observed at 6 months of age among transgenic mice that expressed Tat in the myocardium, concurrent with diastolic and systolic dysfunction [ 84 , 85 ].…”

“…Our data are consistent with prior preclinical findings using Tat-exposed young mice that reported no functional change in heart physiology [ 84 , 85 ]. However, LV dysfunction was observed at 6 months of age among transgenic mice that expressed Tat in the myocardium, concurrent with diastolic and systolic dysfunction [ 84 , 85 ]. These findings support the notion that cardiac biomarkers associated with Tat-mediated abnormalities may appear at younger ages and precede ventricular dysfunction and heart remodeling/failure.…”

“…Similarly, Tat effects on mitochondrial function can also occur in the myocardium. In the Tat-targeted myocardial model, the overexpression of Tat was associated with mitochondrial damage, including swelling, cristae and matrix disruption, and incomplete fusion [ 84 , 86 ]. Tat also impaired mitochondrial quality control, reduced bioenergetic capacity, disrupted mitochondrial membrane potential, and amplified ROS formation in cultured cardiomyocytes [ 34 ].…”

Cardiopatía asociada a infección por VIH

“…Por otro lado, la desregulación del sistema inmunitario y el propio virus intervienen en el desarrollo de un estado proinflamatorio que favorece mecanismos de disfunción endotelial con fenómenos de vasoconstricción y depósito de lípidos, que conducen a la formación de placas ateroscleróticas. Así mismo, se ha detectado aumento de sustancias mediadoras de inflamación, como interleucinas (IL-6, IL-10, factor de necrosis tumoral), por efecto directo del virus 8 . Igualmente, se ha observado un estado protrombótico con alteración de la fibrinólisis endógena y un aumento de niveles de dímero D o del factor von Willebrand que, junto con el estado proinflamatorio, favorecen el incremento de la tasa de eventos aterotrombóticos en estos pacientes.…”