Examination of the Hypothalamic Paraventricular Nucleus in a Rat Model of Chronic Ischaemic Myocardial Injury

Abstract

Ischaemic heart disease, including heart failure (HF) is a leading cause of death worldwide. Despite pharmacological intervention, HF remains a progressive disease with a high mortality rate. The role of the central nervous system in the progression and maintenance of HF is becoming increasingly apparent. In particular, cardiovascular control regions such as the paraventricular nucleus of the hypothalamus appear to contribute to the progression of myocardial injury and development of HF. Neuronal excitation within the paraventricular nucleus results in increased sympathetic output to target organs such as the heart and kidney, which has been shown to exacerbate HF. To date, only the relatively acute paraventricular nucleus response (up to four to six weeks following myocardial infarction) has been assessed. In this study, the long term response (90 days post-myocardial infarction) was investigated. The effect of the angiotensin II type 1 receptor (AT1R) antagonist, losartan, was also assessed on pro-inflammatory cytokine and apoptotic marker levels. Inbred male Lewis rats were randomised into left anterior descending coronary artery ligation surgery (LAD), and sham surgery groups. For the biochemical aspects of the study, the animals were further divided into losartan and vehicle treatment groups. Following surgery, HF was allowed to develop over a period of 90 days. At this time point, signs of both myocardial and renal dysfunction were observed. Within the paraventricular nucleus, pro-inflammatory cytokines and apoptotic markers were found not to be changed in the LAD animals, and were not affected by losartan treatment. In separate immunoflorescence study groups, levels of activated microglia a suspected source of pro-inflammatory cytokines in the paraventricular nucleus, were found to be unchanged in he LAD animals. Interestingly however, AT1R expression in the paraventricular nucleus was found to be significantly increased at 90 days following LAD ligation surgery by 2.7-fold compared to the sham group (P<0.005). Reactive oxygen species levels were also found to be significantly increased in the paraventricular nucleus in the LAD group by 1.6-fold compared to the sham animals (P<0.05). These results show that the paraventricular nucleus response to myocardial ischaemia is still present at 90 days following myocardial injury. Whiel the role of pro-inflammatory cytokines appears to be diminished compared to earlier time points, AT1R expression and reactive oxygen species production remain upregulated. This is consistent with research suggesting that an important interaction between AT1R signalling and reactive oxygen species exists, with downstream mediators also contributing to the pathological response to heart failure. This suggests that the paraventricular nucleus continues to contribute to the progression of HF beyond the acute phase, and may represent a valuable pharmacological target in the future.