HIV-1-Tat excites cardiac parasympathetic neurons of nucleus ambiguus and triggers prolonged bradycardia in conscious rats.
The mechanisms of autonomic imbalance and subsequent cardiovascular manifestations in HIV-1-infected patients are poorly understood. We report here that HIV-1 transactivator of transcription (Tat, fragment 1-86) produced a concentration-dependent increase in cytosolic Ca(2+) in cardiac-projecting parasympathetic neurons of nucleus ambiguus retrogradely labeled with rhodamine. Using store-specific pharmacological agents, we identified several mechanisms of the Tat-induced Ca(2+) elevation: 1) lysosomal Ca(2+) mobilization, 2) Ca(2+) release via inositol 1,4,5-trisphosphate-sensitive endoplasmic reticulum pools, and 3) Ca(2+) influx via transient receptor potential vanilloid type 2 (TRPV2) channels. Activation of TRPV2, nonselective cation channels, induced a robust and prolonged neuronal membrane depolarization, thus triggering an additional P/Q-mediated Ca(2+) entry. In vivo microinjection studies indicate a dose-dependent, prolonged bradycardic effect of Tat administration into the nucleus ambiguus of conscious rats, in which neuronal TRPV2 played a major role. Our results support previous studies, indicating that Tat promotes bradycardia and, consequently, may be involved in the QT interval prolongation reported in HIV-infected patients. In the context of an overall HIV-dependent autonomic dysfunction, these Tat-mediated mechanisms may account for the higher prevalence of sudden cardiac death in HIV-1-infected patients compared with general population with similar risk factors. Our results may be particularly relevant in view of the recent findings that significant Tat levels can still be identified in the cerebrospinal fluid of HIV-infected patients with viral load suppression due to efficient antiretroviral therapy.
Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania;
Eugen
E
Brailoiu
Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania;
Elena
E
Deliu
Department of Internal Medicine, Brandywine Hospital, Coatesville, Pennsylvania;
Romeo A
RA
Sporici
Center for Substance Abuse, Temple University School of Medicine, Philadelphia, Pennsylvania; and.
Khalid
K
Benamar
Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, Pennsylvania gcb004@jefferson.edu.
G Cristina
GC
Brailoiu
D000818:Animals; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D003243:Consciousness / Q000502:physiology*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008845:Microinjections; D010275:Parasympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
D010446:Peptide Fragments; D050916:TRPV Cation Channels; C476722:Trpv2 protein, rat; D054322:tat Gene Products, Human Immunodeficiency Virus; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium
autonomic cardiovascular regulation; cytosolic Ca2+, endoplasmic reticulum; nucleus ambiguus; transient receptor potential vanilloid type 2