Introduction:
Hypertension is a major risk factor for cardiac hypertrophy and heart failure. Genome wide association studies have recently identified single nucleotide polymorphisms in
ATP2B1
, the gene encoding the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), as having a strong association with hypertension risk.
Hypothesis:
PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy.
Aims:
We aim to examine whether there is a
functional
link between PMCA1 and blood pressure regulation, and the development of hypertension. And to determine the impact this link may have on cardiac structure and function.
Methods and Results:
To study the role of PMCA1 we generated a global PMCA1 heterozygous knockout mouse (PMCA1
Ht
). PMCA1
Ht
mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain.
To study the mice under hypertensive stress conditions, 3 month old PMCA1
Ht
and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) or water as a control. Upon angiotensin treatment, PMCA1
Ht
mice showed a significantly greater increase in systolic (62.24±3.05 mmHg) and diastolic pressure (52.68±4.67 mmHg), in comparison to the WT (33.37±2.91 mmHg and 23.94±4.56 mmHg, respectively), P<0.001, n=12.
Moreover, PMCA1
Ht
mice showed a significantly greater hypertrophic response as indicated by a greater heart weight to tibia length ratio, cardiomyocyte cell size (410±18.7 μm
2
), compared to WT mice (340.4±9.8 μm
2
), and increased expression of B-type natriuretic peptide (BNP), 2.36 ± 0.25 fold change, n =5-6, P< 0.01.
Echocardiography showed no significant changes between PMCA1
Ht
and WT mice, in heart rate, and in cardiac function, as indicated by fractional shortening and ejection fraction. In addition, PMCA1
Ht
mice showed no sign of lung congestion as indicated by lung weight to body weight ratio.
Conclusion:
ATP2B1
deletion leads to increased blood pressure and cardiac hypertrophy. This provides functional evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.
The Vascular Effects of Isolated Isoflavones—A Focus on the Determinants of Blood Pressure Regulation
