How Hippo Signaling Pathway Modulates Cardiovascular Development and Diseases

Table 1

Role of the Hippo tumor suppressor pathway in cardiovascular disease.

	Effecter	Methods	Outcomes	Ref.
Cardiovascular development	MST1/2	Cardiac-specific knockout of MST1/2	Enlarged hearts; without alteration of cell size	[15]
	LATS2	Cardiac-specific knockout of LATS2	Enlarged hearts; without alteration of cell size	[15]
	SAV1	Cardiac-specific knockout of SAV1	Enlarged ventricular chambers; thickened ventricular walls; without alteration of cell size	[15]
	YAP	Deplete YAP with Nkx2.5-Cre	Reduced cardiomyocyte proliferative ability; embryonic death at embryonic stage 10.5	[14]
		Overexpress YAP with adenovirus	Cardiomyocytes number increased significantly in newborn mice	[14]
		Cardiac/vascular smooth muscle cell-specific ablation of YAP	Vascular malformations like ventricular septal defect etc.; might result in perinatal fatality	[16]
		Epicardial-specific deletion of YAP/TAZ with Sema3dGFPCre+/−	Attenuated differentiation of the epicardial cell into coronary endothelial cells; embryonic death between E11.5 and E12.5	[17]
Cardiomyocyte hypertrophy and apoptosis	RASSF1A	Generated RASSF1A transgenic (TG)/(L308P) RASSF1A TG mice with adenoviral system; subjected them to pressure overload	Increased MST1 phosphorylation; promotes cardiomyocyte apoptosis; reduced the proliferation ability of fibroblast and cardiac hypertrophy	[19]
	MST1	Upregulation of MST1	Enhanced cardiomyocyte apoptosis	[18]
	MST2	MST2 knockout	Attenuated cardiac hypertrophy	[20]
		MST2 overexpression	Increased cardiac hypertrophy	[20]
	LATS1	Mutation of LATS1 using siRNA	Encouraged cardiac hypertrophy	[22]
	LATS2	Transduced Ad-LATS2 or Ad-LacZ into cultured myocytes; generated LATS2 and DN-LATS2 TG mice using the α-myosin heavy chain promoter	Dose dependently increased apoptosis and reduced cardiac myocyte size in vitro; negatively regulated ventricular chamber size in vivo	[21]
Cardiomyocyte hypertrophy and apoptosis	YAP	Cardiac-specific activation of YAP using adenoassociated virus subtype 9 (AAV9) after MI	Improved cardiac function without causing hypertrophy; enhanced survival	[24]
		Cardiac-specific inactivation of YAP1 using α-MHC Cre recombinase transgenic mice; transduced cardiomyocytes with YAP1 or LacZ adenovirus	Caused increased cardiomyocyte apoptosis in YAP(−/−) at baseline; YAP expression induced cardiomyocyte hypertrophy	[25]
Angiogenesis	LATS1/2	Coinjection of mRNAs encoding Angiomotin p130 and mRNAs encoding LATS2	Induced angiogenesis defects in zebrafish embryos	[30]
	YAP	Knock-down of YAP by siRNA	Significantly reduced the tube formation or sprouting ability of endothelial cells	[28]
		Upregulation of YAP	Induce robust angiogenesis	[28]
Heart regeneration	YAP	Cardiac-specific YAP knockout in MI mice	The infract area was broader and cardiomyocytes were less robust	[32]
		Cardiac-specific upregulation of YAP in MI mice with adenoassociated virus serotype 9	Rescued the cardiomyocyte number and cardiac function	[33]
		Compared Pitx2-deficient mice and Pitx2-overexpressing mice when subjected to apex dissection	Pitx2-deficient mice fail to repair while Pitx2-overexpressing mice showed functional recovery	[35]
Cardiomyocyte autophagy	MST1/2	Inhibition of MST1 phosphorylation with Melatonin, oncostatin M etc.	Promoted cardiac function, enhanced autophagy, and weakened apoptosis	[46–50]
		Phosphorylation of LC3 by MST1/2	Promoted the fusion step of autophagy	[51]
	NDR1	Interact with Beclin1	Function in the early stage of autophagy	[52]