Table 1.
Animal and Cell Models
| Reference | Medication | Cell Type/Model | Disease | Effect on Cells | Tissue/Clinical Effect | Toxicity |
|---|---|---|---|---|---|---|
| Calvier et al., 2019 (30) | Pioglitazone 20 mg/kg/d | PASMC/smLRP1−/− LDLR−/− | PAH | — | Inhibits canonical (Smad3) TGFβ1 signaling; and fully reverses PAH, RVH, and pulmonary vascular remodeling induced by LRP1 deficiency in SMC | — |
| Pioglitazone 10 μM | Human PASMC Murine PASMC |
PAH | Pioglitazone inhibits TGFβ1 canonical (Smad3) phosphorylation and downstream target expression (CTGF), all overactivated in LRP1-deficient PASMC | — | — | |
| Legchenko et al., 2018 (39) | Pioglitazone 20 mg/kg/d | PASMC/SuHx rat | PAH | Reduces obliterative pulmonary vascular remodeling | Fully reverses PAH and RVH; prevents RV dilation and failure; reduces RV mass >50%; reduces RVSP 91→34 mm Hg; and decreases NT-proBNP | No cell toxicity with pioglitazone or rosiglitazone (human PAECs, H9c2 rat cardiomyocytes); no changes in blood glucose concentration |
| Pioglitazone 10 μM | Neonatal rat cardiomyocytes | PAH | Induces fatty acid oxidation and ATP production | — | — | |
| SuHx rat | PAH | Decreases RV glucose uptake and decreases cardiomyocyte size | Prevents RV failure | — | ||
| Calvier et al., 2017 (28) | Pioglitazone 10 μM | HPASMC | PAH | Pioglitazone inhibits TGFβ1–induced proliferation, mitochondrial activation, and TGFβ1 canonical (Smad3/4) and noncanonical (Stat3/FoxO1) phosphorylation cascades | — | — |
| Pioglitazone 20 mg/kg/d by mouth for 5 wk | Transgenic TGFβ1 mice | PAH | — | Inhibits canonical (Smad3/4) and noncanonical (Stat3/FoxO1) TGFβ1 signaling; and fully reverses PAH, RVH, and pulmonary vascular remodeling | — | |
| Behringer et al., 2016 (61) | Pioglitazone 40 mg/kg/d by mouth for 2 wk | MCT rats | PAH | — | Reduces PASP, muscularization of small pulmonary arteries, medial wall thickness, Fulton’s index (RV/LV + S), area of fibrotic RV tissue, and inflammatory markers (macrophage number and osteopontin concentration) and improves survival | — |
| Cardiomyocytes/MCT rats | PAH | Reduces cross-sectional area of cardiomyocytes | Reduces ventricular BNP gene expression | — | ||
| Shiomi et al., 2002 (62) | Pioglitazone 3 mg/kg/d by mouth for 4 wk | Myocardium/CD1 mice with induced myocardial infarction | Myocardial infarction | — | Attenuates progressive LV chamber dilation and dysfunction in a murine model of post-MI heart failure | After 4 wk, plasma glucose concentration was not lowered by pioglitazone; serum AST used to assess potential hepatic toxicity was not increased by pioglitazone |
| Bertero et al., 2014 (33) | Rosiglitazone 20 mg/kg/d by mouth for 3 wk | PASMC overexpression of miR-130a in mice | PAH | — | Reverses miR-130–induced elevated RVSP | — |
| Liu et al., 2012 (63) | Rosiglitazone 10 mg/kg/d | MCT rats | PAH | — | Reduces RVH, PA medial thickening, mitigates 5-HT2BR expression, and inhibits 5-HT2BR–mediated vasoconstriction | — |
| Rosiglitazone 20 mg/kg/d | Chronic hypoxia rats | PH | — | Effects less pronounced than in MCT rats, mitigates 5-HT2BR expression increase, and inhibits 5-HT2BR–mediated vasoconstriction | — | |
| Rosiglitazone pioglitazone 1 μM | PASMC/5-HT–exposed rat | PAH | — | Inhibits upregulation of 5-HT2BR | — | |
| Hansmann et al., 2008 (22) | Rosiglitazone 1 μM | PASMC/SM22α Cre PPARγflox/flox mice | PAH | Reverses SMC proliferation | — | — |
| PASMC human | PAH | Blocks PDGF-BB–induced proliferation of BMPR2 mutant cells | Reverses vascular remodeling | — | ||
| Hansmann et al., 2007 (5) | Rosiglitazone 10 mg/kg/d by mouth for 4 or 10 wk | ApoE−/− mice | PAH | — | Eightfold higher plasma adiponectin concentrations, improves insulin sensitivity, and induces complete regression of PAH, RVH, and abnormal PA muscularization | Mild LV dilation and increased LV mass in apoE-deficient mice, and lower hematocrit in treated mice |
Definition of abbreviations: 5-HT = 5-hydroxytryptamine (or serotonin); 5-HT2BR = serotonin receptor 2B, serotonin; ApoE = apolipoprotein E; AST = aspartate aminotransferase; BMPR2 = bone morphogenetic protein receptor 2; CTGF = connective tissue growth factor; LDLR = low-density lipoprotein receptor; LV = left ventricle; HPASMC = human pulmonary arterial smooth muscle cells; MCT = monocrotaline; MI = myocardial infarction; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; PA = pulmonary artery; PAEC = pulmonary artery endothelial cells; PAH = pulmonary arterial hypertension; PASMC = pulmonary artery smooth muscle cells; PASP = pulmonary arterial systolic pressure; PDGF-BB = platelet-derived growth factor BB; PH = pulmonary hypertension; PPARγ = peroxisome proliferator–activated receptor-γ; RV = right ventricle; RVH = right ventricular hypertrophy; RVSP = right ventricular systolic pressure; S = septum; SMC = smooth muscle cells; smLRP1 = smooth muscle low-density lipoprotein receptor–related protein 1; Stat3 = signal transducer and activator of transcription 3; SuHx = Sugen 5416/hypoxia; TGFβ1 = transforming growth factor β1.