High blood pressure and high cholesterol are good friends, often accompanying each other in humans. Medical science has been trying to establish exactly how one influences the other but has found no clear answer yet. But, interestingly, in hypertensive rats, high blood pressure (BP) was found correlated with lower cholesterol compared with the ‘control’ group of rats with normal BP.
Research by Prof Nitish Mahapatra and his team at the IIT-Madras biotechnology department determined that a certain genetic pattern helps this inverse correlation.
For the sake of testing, the spontaneously hypertensive rat (SHR) model was developed about 60 years ago in Japan. “These rats display high blood pressure from 5-6 weeks of age (corresponding to 15-20 human years) and are widely studied for understanding cardiovascular disease pathogenesis as well as in drug development,” says Mahapatra.
The Wistar-Kyoto (WKY) rat is normotensive, showing normal blood pressure. The IIT-Madras team looked into the molecular or genetic basis for the inverse correlation between BP and cholesterol by ‘sequencing the genes’ of SHRs and WKYs.
Sequencing helps find the exact order of nucleotides — the building blocks of DNA. The four nucleotides — A (Adenine), T (Thymine), G (Guanine) and C (Cytosine) — are arranged in a different order for each of our genes. “We humans have some 20,000 genes — similar to rats and mice,” says Mahapatra. “Our research focused on the HMG-CoA reductase, the enzyme responsible for the synthesis of cholesterol... in deciding how much is produced in our liver.” The commonly used cholesterol-lowering drug family — statins — targets this enzyme.
The idea was to see if there was any difference in the DNA sequence of the HMG-CoA reductase gene between the SHRs and WKYs. After close to six years of research, the team identified a key difference in the ‘regulatory region’ of this gene. “For a particular gene, there are regions that determine whether more or less of the protein would be produced,” explains Mahapatra.
“Several nucleotides are different for the SHRs compared with the normotensive WKYs,” he says. At a specific regulatory region of the HMG-CoA reductase gene, the team detected a G nucleotide in SHRs and an A in WKYs. This difference at the ‘promoter region’ is “responsible for the lower quantum of HMG-CoA reductase, leading to lower cholesterol in SHRs”.
“For the first time, to the best of our knowledge, this study could explain the molecular basis of diminished cholesterol level in this animal model of human hypertension,” he says. “Further studies are anticipated to result in new therapies for heart disease,” he adds.
The study has been published in Journal of Molecular and Cellular Cardiology, the official journal of the International Society for Heart Research.
Now, the team is exploring the role of other genes involved in cholesterol synthesis or the metabolism for high blood pressure in SHR animals. “We are working on identifying unique DNA elements that may serve as master switches to lower cholesterol level in SHRs.”
So, in the future, could doctors flip a ‘switch’ to lower cholesterol levels? “Theoretically, yes. Though that hope is currently the realm of science fiction.”