C1q/TNF-α–Related Protein 1 (CTRP1) has recently been shown to act as a blood pressure regulator, as it induces vasoconstriction. In the aorta, CTRP1 facilitates recruitment of angiotensin II receptor 1 (AT1R) to plasma membrane, through activation of the AKT/AS160 signaling pathway. This leads to activation of the Ras homolog gene family (Rho)/Rho kinase (ROCK) signaling pathway, resulting in vasoconstriction. Accordingly, mice overexpressing Ctrp1 have hypertensive phenotype. Patients with hypertension also display higher circulating CTRP1 levels, compared to healthy individuals, indicating that excessive CTRP1 may affect development of hypertension. Conversely, CTRP1 is regarded as an ‘innate blood pressure modulator’ because CTRP1 increases blood pressure under dehydration to prevent hypotension. Mice lacking Ctrp1 fail to maintain normotension under dehydration conditions, resulting in hypotension, suggesting that CTRP1 is an essential protein for maintaining blood pressure homeostasis. In conclusion, CTRP1 is a novel, anti-hypotensive vasoconstrictor that increases blood pressure during dehydration-induced hypotension.
Hypertension is a serious public health problem, affecting approximately one-fourth of the adult population of industrialized countries. Even with our present understanding of the pathophysiology of hypertension, most patients are classified with essential hypertension because of unclear etiology in approximately 90% of cases (Carretero OA
In 2008, Jeon
To dissect the physiological function and molecular mechanism of CTRP1 in regulation of blood pressure, CTRP1 transgenic (CTRP1 TG) and inducible knockout (CTRP1 KO) mice were generated, since conventional CTRP1 KO mice showed embryonic lethality. CTPR1 TG mice were hypertensive while CTRP1 KO mice had a hypotensive phenotype, indicating that CTRP1 positively regulated blood pressure. Structural abnormalities in cardiovascular and renal systems are not likely to be the cause of increased blood pressure by CTRP1 because only aged-CTRP1 TG mice showed anatomic and functional alterations of the heart without changes in levels of plasma/urine electrolytes and hematocrit. It is likely that life-long hypertension in CTRP1 TG mice induces structural changes in cardiovascular tissues. Interestingly, these anatomical changes in aged-CTRP1 TG mice are similar to those observed in patients with chronic hypertension, suggesting the CTRP1 TG mouse model could be applied as a human hypertension mimicking rodent model.
Although CTRP1 does not affect the vascular structure, CTRP1 directly influences vascular tone, which confers the balance between relaxation (vasorelaxation) and contraction (vasoconstriction) in vascular smooth muscle. Thoracic aortic ring contraction assays revealed that CTRP1 induces vasoconstriction. This result indicated that CTRP1 is a potent vasoconstrictor, and this is the likely mechanism by which CTRP1 increases blood pressure. Vasoconstriction is exerted by phosphorylated myosin light chain (MLC), which induces cytoskeleton reorganization. The Ras homolog gene family (Rho)/Rho kinase (ROCK) signaling pathway upregulates MLC phosphorylation (Amano M
Although CTRP1 is not an angiotensin II receptor 1 (AT1R) ligand, CTRP1 activates Rho/ROCK signaling pathway by enhancing trafficking of AT1R to the plasma membrane. Administration of AT1R inhibitor, losartan, effectively decreased blood pressure in CTRP1 TG mice, and CTRP1 KO mice were less sensitive to angiotensin II (ANGII)-elicited hypertension compared to WT mice, indicating that AT1R mediates Rho/ROCK-dependent vasoconstriction by CTRP1. In VSMCs, CTRP1 treatment increased phosphorylation of AKT and its downstream target, AKT substrate of 160 kDa (AS160) which is known to facilitate the trafficking of various transmembrane proteins to the plasma membrane, including glucose transporter 4 (GLUT4) (Kane S
Notably, production and secretion of CTRP1 were increased by glucocorticoids in skeletal muscle under water restriction-and diuretic-induced dehydration conditions.
Additionally, CTRP1 KO mice failed to maintain normotension under dehydration conditions, resulting in hypotension. These observations suggest the basic role of CTRP1 is to prevent dehydration-induced hypotension by increasing blood pressure through vasoconstriction. It is well-known that dehydration causes blood pressure to drop, which is also known as hypotension. With other hormones, glucocorticoids are secreted from adrenal glands to increase blood pressure and maintain blood pressure homeostasis against dehydration-induced hypotension (Dampney RA
Together, these findings demonstrate that CTRP1 acts as a humoral and innate vasoconstrictor to prevent hypotension during dehydration and is produced in response to glucocorticoid production (Diagram 1). Therefore, targeting CTRP1 could represent a new strategy to treat hypo- and hypertension, depending on the particular physiological condition.