Table 2.

Role of PROK in preclinical models of cardiac and neuronal diseases

System	Models	Functions
Cardiovascular (CV) system
Preclinical CV disease models	MI Infarction	PKR1 agonist IS20 has cardiovascular (CV) protective effect, increases capillary network Preclinical CV development, increases EPDCs number and disease models improves CV functions [58].
	Doxorubicin (DOX)-mediated cardiotoxicity	IS20 protects cardiomyocytes endothelial cells and EPDCs, provides vascular stability, by increasing AKt survival and antioxidant pathways and improves CV functions [123].
	Breast cancer mice models	No alteration on antitumor efficacy of DOX by PKR1 agonist [123].
	Global PKR1 knockout –PKR1-KO)	Dilated cardiomyopathy, kidney atrophy urine retention [63].
		Obesity, diabetes [97].
Knockout mice models	Adipose restricted PKR1-KO	Obesity [97].
	Endothelial restricted PKR1-KO	Lipodyslipidemia, insulin insensitivity, CV and renal disorders [62].
	Epicardium restricted PKR1-KO prenatal	Embryonic lethality due to error in epicardial cardiomyocyte communication and lack of EMT
	Epicardial originated fibroblast progenitor restricted PKR1-KO postnatal	Development of epicardial adipose tissue (EAT) perivascular adipose tissue (PAT), loss of vascular network, impaired cardiac function, arrhythmia [64].
	Epicardin positive renal progenitor restricted PKR1-KO	Abnormal glomerular structure, atrophic kidney, urine retention [93].
	Overexpression of PKR1 cardiomyocytes of transgenic mice hearts	No abnormalities in cardiomyocytes, but increased vascularization and activation of adult EPDCs proliferation and differentiation into vascular cell type [70].
Transgenic overexpression mice models	Overexpression of PKR2 in cardiomyocytes of transgenic mice hearts	Hypertrophic cardiomyopathy and endotheliopathy [71]
CNS
Cerebral disease models	Cerebral ischemia	PROK2 at high dose plays neuroprotective role models via activating ERK/Akt signaling [104], while at low dose increases the infarct volume [103].
Neurodegenerative models	Parkinson’s diseases	PROK2 via PKR1 protects dopaminergic neurons and prevents neurodegeneration [110]. PKR1 agonist, IS20 controls neuron-astrocyte A2 protective signaling, leads to an increase in antioxidant and anti-inflammatory proteins [117].
		OB defects, Kalmann syndrome like phenotype [80].
Knockout mice models	PROK2 null mice	Low circadian rhythmicity [126] affecting physiological and behavioral parameters, including sleep/wake cycle [125], locomotor activity, and anxiolytic and antidepressant-like effects [127], food intake and thermoregulation [128].
		Partial deletion of PROK2 in the MOB promotes insulin resistance, and increases food intake in vivo [100]
	PKR1 null mice	Feeding [98] [99]
	PKR2 deficient mice	OB developmental abnormalities [77], circadian rhythm dysregulation [129], Kalmann syndrome like phenotype, abnormal pain sensation [130].
Transgenic overexpressing models	PK2 overexpressing transgenic mice and zebrafish	Augmentation of sleep in light and suppression of sleep in dark [131] via PKR2[132]