Table 4.

Autophagy and mitophagy in pulmonary hypertension

Experimental Models	Evidence of Altered Autophagy	Protective Effect of Autophagy on Pulmonary Hypertension	Reference
Human PH	Lungs from human patients with pulmonary hypertension showed increased LC3B levels and autophagosomes prompting study of the role of autophagy in PH.	Not assessed	Lee et al. 2011
	Mitochondrial dysfunction is also known to be involved in the pathogenesis of pulmonary hypertension as mitochondrial fragmentation is increased in the PASMCS of patients with PAH.		Marsboom et al. 2012
Rat chronic hypoxia	Hypobaric hypoxia for 2 wk did not change LC3B-II.	17β-Estradiol increased LC3-II in the lungs exposed to hypobaric hypoxia, and attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated inhibition of pulmonary vascular remodeling.	Lahm et al. 2012
Mouse chronic hypoxia	LC3B is increased in the lung in mice exposed to hypoxia for 3 wk, and increased in PAECs and PASMC exposed to hypoxia for 24 h.	Lc3b-deficient mice had exaggerated PH in response to hypoxia, suggesting that autophagy is protective against chronic hypoxia-induced PH.	Lee et al. 2011

Experimental models	Evidence of altered autophagy	Detrimental effect of autophagy on pulmonary hypertension	Reference
Rat monocrotaline	LC3B-II is increased and p62 is decreased and a decreased in p62 in the rat lung in response to monocrotaline.	Inhibition of autophagy by chloroquine further increased LC3B-II and restored p62, concurrent with an attenuation of pulmonary hypertension, right ventricular hypertrophy, and vascular remodeling. In vitro chloroquine or siRNA of Atg5 inhibits proliferation in rat PASMCs.	Long et al. 2013
Lamb	In a model of PPHN in newborn lambs with intrauterine ductus arteriosus constriction, PAEC isolated from PPHN lambs exhibited increased LC3-II but no longer responded to serum starvation induction.	Chloroquine, 3-MA, or Becn1 knockdown decreased DHE fluorescence after ATP simulation, improved angiogenesis and scratch recovery, indicating that autophagy impairs angiogenesis and recovery in these PAEC.	Teng et al. 2012
Rat PAH induced by Sugen hypoxia-normoxia	A single subcutaneous injection of Sugen-5416 on day 1 and exposed to 3 wk of normobaric hypoxia, followed by reexposure to normoxia for 5 additional weeks elevated LC3-II in the RV.	DHEA decreased LC3-II and improved diastolic heart failure phenotypes.	Rawat et al. 2014
Mouse PAH induced by pulmonary artery constriction	Increased LC3 and p62 were associated with RV failure.	Folic acid decreased the raise in LC3 and p62 and attenuated RV failure.	Qipshidze et al. 2012
Human PH, CoCl2 and chronic hypoxia-induced PH in rat	In idiopathic human PAH lungs, Ser616 phosphorylated active form of DRP1 is elevated in blood vessels, HIF1α is activated in lungs and PASMCs.	In CoCl2 and chronic hypoxia-induced pulmonary hypertension in rats, inhibition of DRP1 by Mdivi-1 decreased pulmonary hypertension.	Marsboom et al. 2012
Human PAH, female rats exposed to chronic hypoxia+Sugen-5416 or monocrotaline	PASMC from human PAH and rat exposed to chronic hypoxia+Sugen-5416 or monocrotaline have less MFN2 and more fragmented mitochondria.	Ad-Mfn2 and Mdivi-1 attenuated PAH phenotypes in rats exposed to hypoxia+Surgen-5416, and their effects appear to be additive.	Ryan et al. 2013
human PAH, mice exposed to IH	PINK1 is elevated in human PAH and in mice in response to either Ucp2 knockout or IH.	Silencing Pink1 increased right ventricle systolic pressure after IH, but decreased the increase of right ventricle systolic pressure and right ventricle hypertrophy induced by Ucp2 knockout after IH, thus indicating a protective role of PINK1 in response to IH but a detrimental role in response to IH when Ucp2 is impaired.	Haslip et al. 2015