Transcriptomic analysis of a mouse model for group 2 and 3 pulmonary hypertension

The most frequent and lethal types of pulmonary hypertension (PH) are group 2 (based onheart disease) and group 3 (based on lung disease). Group 2 can develop during valvularheart disease and/or left ventricular dysfunction when elevated left heart filling pressure istransmitted retrogradely to the pulmonary circulation. Group 3 PH is related to interstitial lungdisease and/or hypoxia in patients with COPD or sleep apnea. Interestingly, only a minor partof individuals with heart or lung disease develops PH. Therefore, it has been hypothesized thata "second hit", an additional factor that triggers the onset of disease, is required. Because thedevelopment of group 2 or 3 PH indicates a poor prognosis it is very important to identify potential"second hits". In previous studies the search for second hit mechanisms focused ongenetic mutations or vascular injury and inflammation. As heart and lung disease is both verycommon and many patients are categorized having an overlap diagnosis of group 2 and 3 PH,we hypothesized that also these could act as "second hits".To investigate this, we established a "second hit" mouse model by combining left heart diseaseinduced by mild TAC surgery and lung disease induced by short hypoxic treatment. AfterTAC surgery alone left heart disease, right ventricular fibrosis as well as lung remodeling developedalready after 3 weeks, while elevated right ventricular systolic pressure (RVSP) indicatingPH and RV hypertrophy was only detected after 8 weeks. To apply a "second hit" wecombined TAC for 3 weeks with hypoxic exposure (HX) for the last 10 days of the protocol.Only the combination of both treatments resulted in enhanced RVSP and therefore PH afterthe selected 3-week time period. At this time point RV and lung remodeling of combined TACHX was unaltered compared to TAC alone but RNAseq analysis of RVs from TAC HX specificallyrevealed functional, cell biological and metabolic processes characteristic for extensivecardiac remodeling.