Key result
A cardiac-specific null mutation of Prdm16 in female mice caused significant hypotension and cardiac hypertrophy, which was mediated by increased expression of nitric oxide synthase 1 (NOS1).
Why the study?
The molecular mechanisms underlying blood pressure changes in heart failure are not clearly understood.
Does cardiac loss of Prdm16 cause hypotension in mice, and is it mediated by NOS1?
Does cardiac loss of Prdm16 cause hypotension in mice, and is it mediated by NOS1?
p-value: p=<0.05
A cardiac-null mutation of Prdm16 in mice causes hypotension and cardiac hypertrophy, with the hypotension being driven by increased NOS1 expression.
Does not support clinical translation; leaves open whether cardiac Prdm16-NOS1 regulates human blood pressure or hypertrophy.
Hypertension or hypotension prevails as a comorbidity in patients with heart failure (HF). Although blood pressure (BP) is an important factor in managing the mortality of HF, the molecular mechanisms of changes in BP have not been clearly understood in cases of HF. We and others have demonstrated that a loss in PRDM16 causes hypertrophic cardiomyopathy, leading to HF. We aimed to determine whether BP is altered in mice that experience cardiac loss of Prdm16 and identify the underlying mechanism of BP-associated changes. BP decreased significantly only in female mice with a cardiac-null mutation of Prdm16 compared with controls, by an invasive protocol under anesthesia and by telemetric method during conscious, unrestrained status. Mice with a cardiac loss of Prdm16 had higher heart-to-body weight ratios and upregulated atrial natriuretic peptide, suggesting cardiac hypertrophy. Plasma aldosterone-to-renin activity ratios and plasma sodium levels decreased in Prdm16-deficient mice versus control. By RNA-seq and in subsequent functional analyses, Prdm16-null hearts were enriched in factors that regulate BP, including Adra1a, Nos1, Nppa, and Nppb. The inhibition of nitric oxide synthase 1 (NOS1) reverted the decrease in BP in cardiac-specific Prdm16 knockout mice. Mice with cardiac deficiency of Prdm16 present with hypotension and cardiac hypertrophy. Further, our findings suggest that the increased expression of NOS1 causes hypotension in mice with a cardiac-null mutation of Prdm16. These results provide novel insights into the molecular mechanisms of hypotension in subjects with HF and contribute to our understanding of how hypotension develops in patients with HF.
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Kang et al. (2022) studied Cardiac hypertrophy and hypotension. Cardiac-specific Prdm16 knockout vs. Wild-type/control mice was evaluated on Blood pressure (mean BP, SBP, DBP) (p=<0.05). A cardiac-specific null mutation of Prdm16 in female mice caused significant hypotension and cardiac hypertrophy, which was mediated by increased expression of nitric oxide synthase 1 (NOS1).
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