Aortic constriction induces hypertension and cardiac hypertrophy via (pro)renin receptor activation and the PLC‑β3 signaling pathway

Abstract

The (pro)renin receptor [(P)RR] serves an important role in cardiovascular complications. However, the precise mechanisms of (P)RR in the heart remain obscure. The authors hypothesized that overexpression of (P)RR would be associated with activation of the relevant signal pathway which could lead to organ injury. The aim of the present study was to test the role of cardiac (P)RR and its potential signaling pathway components including phospholipase C (PLC), protein kinase C (PKC), extracellular signal-regulated kinase (ERK)1/2 and Raf-1 proto-oncogene, serine/threonine kinase (Raf-1). Hypertension and cardiac hypertrophy were induced by partial abdominal aortic ligation in Sprague-Dawley rats. The expression levels of cardiac (P)RR, PLC-β3, PKC, ERK1/2 and Raf-1 were measured following administration of the handle region peptide (HRP) and PLC-β3 inhibitor U73122. The expression of (P)RR and PLC-β3 significantly increased in the left ventricle (P<0.05). Levels of PKC-α, ERK1/2 and Raf-1 in the heart rose significantly (P<0.05). HRP and U73122 significantly decreased the levels of cardiac (P)RR and PLC-β3. Furthermore, levels of PKC-α, ERK1/2 and Raf-1 were also decreased (P<0.05). Cardiac parameters, blood pressure and plasma Angiotensin (Ang) I and Ang II levels were altered significantly (P<0.05). The results demonstrated that hypertension induced by aortic restriction activated the (P)RR in the heart. This action led to hypertension and cardiac hypertrophy via the (P)RR-PLC-β3-PKC-ERK1/2-Raf-1 signaling pathway. These results provide a mechanism by which elevated (P)RR levels in hypertension may contribute to the development of cardiac remodeling.

Upregulation of Phospholipase C Gene Expression Due to Norepinephrine-Induced Hypertrophic Response

“…In volume overload-induced cardiac hypertrophy subsequent to an arteriovenous shunt, specific increases in PLC β 1 and PLC γ 1 isozyme gene, protein contents, and activities [ 62 , 63 ] have been observed. A similar activation of PLC β 3 has been observed in pressure overload-induced cardiac hypertrophy due to aortic constriction in the rat [ 64 ]. In contrast, the activation of PKC isozymes has been observed in pressure overload cardiac hypertrophy in the guinea pig, subsequent to ligation of the descending thoracic artery, without any changes in PLC β 1 and Gαq protein contents [ 65 ].…”

Cholecystokinin Expression in the Development of Myocardial Hypertrophy

“…Myocardial hypertrophy is induced by heart overload and characterized by increased myocyte size and the incrassate cardiac wall and thought to be an adaptive response to cardiac wall stress resulting from the cardiac pressure afterload and volume overload, including hypertension [ 12 ], aortic constriction [ 13 , 14 ], and valve regurgitation [ 15 , 16 ]. MH is first described by Cotton in 1914 [ 17 ].…”

Cardiovascular aspects of the (pro)renin receptor: Function and significance

“…Sprague‐Dawley rats with partial abdominal aortic ligation exhibited hypertension and cardiac hypertrophy accompanied by significantly increased PRR and phospholipase C‐β3 (PLC‐β3) expression in the left ventricle 35 . Both PRR inhibition by HRP and PLC‐β3 inhibitor U73122 significantly decreased BP and attenuated cardiac hypertrophy in rats with aortic constriction, accompanied by reduced cardiac PLC‐β3, PKC‐α, ERK1/2, and Raf‐1 expression, and plasma AngI and AngII concentrations 35 (the values of these peptides in rat plasma are unusually higher than typically reported especially in normal conditions and needed to be validated. Necessary extraction is recommended.).…”

“…These results suggest that cardiac PRR plays an important role in aortic constriction‐induced hypertension and cardiac hypertrophy by activating the PLC‐β3/PKC/ERK1/2/Raf‐1 signaling pathway (Figure 1). 35 …”